Inhibitors of TRPC6

ABSTRACT

The invention relates to compounds of formula (I), 
                         
and pharmaceutically acceptable salts thereof, wherein R 1  to R 7 , A, Y and L are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

CROSS REFERENCE TO RELATED APPLICATION(S)

This Application is a Non-Provisional Application and claims priorityunder 35 USC 119(e) of U.S. Application Ser. No. 62/628,313, filed Feb.9, 2018, and U.S. Application Ser. No. 62/577,883, filed Oct. 27, 2017.The entire contents of these applications are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compounds, compositions,and methods for the treatment of cardiac and respiratory conditions,renal disease, liver disease, muscular dystrophy, fibrotic disorders,pain, ischemia or ischemic reperfusion injury, and cancer, as well asinhibiting the Transient Receptor Potential C6 ion channel (TRPC6).

BACKGROUND

A variety of ion channel proteins exist to mediate ion flux acrosscellular membranes. The proper expression and function of ion channelproteins is essential for the maintenance of cellular function,intracellular communication, and the like. An important aspect ofachieving cellular homeostasis is the maintenance of appropriate ionconcentrations in various cell types during development and in responseto numerous stimuli. Large numbers of diverse types of ion channels actto maintain cellular homeostasis by moving ions into and out of cellsacross the plasma membrane, and within cells by moving ions acrossmembranes of intracellular organelles including, for example, theendoplasmic reticulum, sarcoplasmic reticulum, mitochondria andendocytic organelles including endosomes and lysosomes. Numerousdiseases are the result of dysregulation of membrane potential oraberrant calcium handling. Given the central importance of ion channelsin modulating membrane potential and ion flux in cells, identificationof agents that can promote or inhibit particular ion channels is ofgreat interest as research tools and as possible therapeutic agents.

One such channel is the Transient Receptor Potential C6 (TRPC6) channel.TRPC6 belongs to the larger family of TRP ion channels (see, Desai etal., 2005 Eur J Physiol 451:11-18; Clapham et al., 2001 Nat Neurosci2:387-396; Clapham, 2003 Nature 426: 517-524; Clapham et al., 2002IUPHAR Compendium). TRPC6 is a calcium permeable channel, specifically anon-selective calcium permeable cation channel. In addition to calciumions, TRPC6 channels are permeable to other cations, for example sodium.Thus, TRPC6 channels modulate not only intracellular calciumconcentration, but also membrane potential by modulating the flux ofcations including calcium and sodium ions. Although non-selective cationchannels such as TRPC6 modulate, among other things, calcium ion flux,they are mechanistically distinct from voltage-gated calcium channels.Generally, voltage-gated calcium channels respond to depolarization ofthe potential difference across the membrane and can open to permit aninflux of calcium from the extracellular medium and a rapid increase inintracellular calcium levels or concentrations. In contrast,non-selective cation channels such as TRPC6 are generally signaltransduction gated, long-lasting, and produce less rapid changes in ionconcentration. They show increased activity in response to theproduction of the second messenger, diacylglycerol (Hofmann et al.,1999). In addition, TRPC6 can respond to changes in pressure. Thesemechanistic differences are accompanied by structural differences amongvoltage-gated and cation permeable channels. Thus, although many diversechannels act to regulate ion flux and membrane potential in various celltypes and in response to numerous stimuli, it is important to recognizethe significant structural, functional, and mechanistic differencesamong different classes of ion channels.

TRPC6 function has been implicated in, among other things, themodulation of myogenic tone. TRPC6 is highly expressed in smooth musclecells, vascular smooth muscle cells, cardiomyocytes, pulmonary arteries,the aorta, heart, liver, brain, and kidney. The expression of TRPC6,along with experiments conducted in knock-out mice and cells in culture,suggest that TRPC6 may provide a useful target for the treatment ofhypertension and other cardiac and vascular conditions, preeclampsia.

Mutation in the human TRPC6 channel can cause focal segmentalglomerulsclerosis (FSGS) (Winn et al., 2005, Reiser et al., 2005). Thesemutations that are reported to be gain-of-function (Reiser et al.,2005), are sufficient to induce disease. In addition, elevated TRPC6expression has been associated with nephrotic syndrome, minimal changedisease, and diabetic nephropathy (Moller et al., 2006, Ilatovskaya etal., 2013, Thilo et al., 2011), or other kidney conditions.

Based on its expression and work implicating it in TGF-B signaling,TRPC6 is also thought to be important in respiratory conditions,restenosis, liver disease, muscular dystrophy, fibrotic disorders, pain,ischemia and ischemic reperfusion injury, and certain forms of cancer.

Yue et al. studied TRPC6 channels for a role in mediating the pulmonaryartery smooth muscle cell proliferation that can lead to idiopathicpulmonary arterial hypertension (IPAH). Pulmonary vascular medialhypertrophy caused by excessive pulmonary artery smooth muscle cell(PASMC) proliferation is a major cause for the elevated pulmonaryvascular resistance in patients with IPAH. The authors found that TRPC6was highly expressed and TRPC3 was minimally expressed in PASMC fromhealthy lung tissue. However, in lung tissue from IPAH patients, mRNAand protein expression of TRPC3 and TRPC6 were significantly elevated incomparison to that in normotensive patients. Furthermore, proliferationof PASMC cells derived from IPAH patients was markedly reduced followingincubation with TRPC6 siRNA. Based on these results, the authorsconcluded that TRPC6 may be important in mediating proper PASMCproliferation, and that dysregulation of TRPC6 may lead to increasedPASMC proliferation and pulmonary vascular medial hypertrophy observedin IPAH patients (Yu et al., 2004 Proc Natl Acad Sci 101(38):13861-6).Further support is provided by the observation that in IPAH patients thefrequency of a single-nucleotide polymorphism in the promoter of TRPC6which increases expression was significantly higher when compared tonormal subjects (Yue, et al., 2009 Circulation 119: 2313-22).

Additional evidence implicating TRPC6 dysregulation in IPAH comes fromstudies of bosentan, a dual endothelin receptor blocker, that has beenused clinically to treat IPAH. This inhibitor decreases proliferation ofPASMCs, but the mechanism by which this occurs is unclear.Interestingly, bosentan both decreases proliferation of PASMC and alsodecreases expression of TRPC6 in lung tissue of IPAH patients (Kunichikaet al., 2004 Am J Respir Crit Care Med 170(10):1101-7).

Chronic exposure of cigarette smoke (CS) to rats resulted in an increasein TRPC6 mRNA and protein expression in distal pulmonary arteries andsimilar effects were observed using PASMCs in vitro. Nicotine treatmentof cultured rat PASMCs upregulated TRPC6 expression and increasedintracellular calcium levels, both of which were reduced by TRPC6 siRNAsilencing (Wang et al., 2014 Am J Physiol Cell Physiol 306:C364-73).These results suggest a role for TRPC6 in CS-induced lung injury.

Evidence supports a role of TRPC6 in additional pulmonary disorders. Inalveolar macrophages from patients with chronic obstructive pulmonarydisease (COPD), TRPC6 expression was found to be elevated when comparedwith controls (Finney-Hayward et al., 2010 Am J Respir Cell Mol Biol43:296-304). In human cystic fibrosis epithelial cells, theTRPC6-mediated calcium influx is abnormally increased and may contributeto the hypersecretion of mucus. siRNA-TRPC6 was able to reduce thisabnormal calcium influx (Antigny et al. 2011 Am J Resp Cell Mol Biol,44:83-90). In mouse lung fibroblasts, the pro-fibrotic activity of PDGFis dependent on the activation of TRPC6, suggesting that TRPC6inhibition would reduce lung fibrosis (Lei et al., 2014 Biomaterials35:2868-77). A role of TRPC6 in pulmonary endothelial cell function wasdemonstrated in mouse lung models of ischemia-reperfusion induced-edemaand lipopolysaccharide-induced inflammation in which TRPC6 deficiencywas able to reduce acute lung injury by preserving endothelial barrierfunction (Weissmann et al., 2011 Nat Comm, 3:649-58 and Tauseef et al.,2012 J Exp Med 209:1953-68).

Recent studies also implicate the role of TRPC6 in other cardiacconditions, including cardiac hypertrophy. The hearts of patients withdilated cardiomyopathy have elevated TRPC6 mRNA expression when comparedwith normal hearts (Kuwahara et al., 2006 J Clin Invest 116:3114-26). Inmouse models of cardiac hypertrophy, TRPC6 cardiac mRNA levels areelevated by pressure overload (Kuwahara et al., 2006 J Clin Invest116:3114-26), chronic isoproterenol treatment (Xie et al., 2012 NatCommun 3:1238), and uremic cardiomyopathy induced by partial nephrectomy(Xie et al., 2015 J Am Soc Nephrol 26:1150-60). Furthermore,cardiac-specific overexpression of TRPC6 in the cardiomyoctes oftransgenic mice induced cardiac hypertrophy and premature death(Kuwahara et al., 2006 J Clin Invest 116:3114-26).

Wu and colleagues found that transgenic mice expressingdominant-negative TRPC6 in a cardiac-specific fashion had an attenuatedcardiac hypertrophic response following either neuroendocrine agonistinfusion or pressure-overload simulation, indicating that TRPC6 is acomponent of channel complexes that are essential mediators ofhypertrophy (Wu et al., 2010 Proc Natl Acad Sci. 107:7000-05). Smallmolecule drugs targeting TRPC6 have also recently begun to show promisein treating cardiac conditions. For example, Seo and coworkersdemonstrated that TRPC6 and TRPC3 antagonists (GSK2332255B andGSK833503A) exhibited dose-dependent inhibition of cell hypertrophysignaling in neonatal and adult cardiac myocytes (Seo et al., 2014 ProcNatl Acad Sci 111:1551-1556). Similarly, mice deficient for TRPC6 wereprotected from isoproterenol-induced cardiac hypertrophy (Xie et al.,2012 Nat Commun 3:1238).

Reducing TRPC6 activity may be beneficial for the treatment ofcardiovascular disease. In vitro, atheroprone shear stress-inducesincreased TRPC6 mRNA levels in human vascular endothelial cells (EC)when compared to atheroprotective flow conditions (Thilo, et al., 2012Hypertension 59:1232-40). EC migration is important for healing afterarterial injury, and lysophosphatidylcholine-mediated inhibition of ECmigration was prevented in vitro in cells from TRPC6 deficient mice.Furthermore, high cholesterol diet combined with carotid injury did notimpair healing in TRPC6 deficient mice when compared with wild-typecontrols (Rosembaum et al., 2015 J Vasc Surg 62:1040-47 and Chaudhuri etal., 2008 Mol Biol Cell 19: 3203-11). Similarly, balloondilatation-induced injury of human internal mammary arteries ex vivoresulted in increased TRPC6 mRNA levels when compared with undilatedarteries (Bergdahl et al., 2005 Am J Physiol Cell Physiol 288:0872-80).Apoptosis of endothelial cells is involved in the initiation andprogression of atherosclerotic lesions, and oxidized low-densitylipoprotein-induced apoptosis of human aortic ECs was demonstrated to bedependent on TRPC6 (Zhang et al., 2015 Sci Rep 5:9401-10). In a ratmodel of forebrain ischaemia, TRPC6 mRNA levels were increased invascular SMCs and correlated with reduced cerebral blood flow (Johannsonet al., 2015 Acta Physiol 214:376-89).

Studies by Reiser, Winn, and Schlöndorff identified mutations in TRPC6in patients as being causative in FSGS (Reiser et al., 2005 Nature Genet37:739-744; Winn et al., 2005 Science 308:1801-1804; Schlondorff et al.,2009 Am J Physiol Cell Physiol 296:C558-69). Subsequent studiesidentified additional TRPC6 mutations associated with steroid-resistantnephrotic syndrome (C. Sadowski et al., 2014 J Am Soc Nephrol26:1279-89). Further studies demonstrated that TRPC6 is important innormal podocyte function by controlling calcium influx and nuclearfactor of activated T cell activation in which elevated current throughthe channel is associated with renal injury and the induction ofproteinuria (Moller et al., 2007 J Am Soc Nephrol 18:29-36 andSchlondorff et al., 2009 Am J Physiol Cell Physiol 296:C558-69). Inaddition to Gain of Function mutations, it has been shown thatexpression of TRPC6 is elevated in human chronic kidney diseasesincluding FSGS, minimal change disease, membraneous glomerulonephritis,and diabetic nephropathy (Moller et al., 2007 J Am Soc Nephrol 18:29-36and Thilo et al., 2011 Nephrol. Dial. Transplant 27:921-9) as well as inmouse models of podocyte injury (Moller et al., 2007 J Am Soc Nephrol18:29-36). TRPC6 deficient mice have been demonstrated to have reducedangiotensin II (Ang II)-induced albuminuria (Eckel et al., 2011 J Am SocNephrol 22:526-35) whereas transgenic podocyte-specific expression ofhuman GoF mutations in mice induces albuminuria and glomerular lesions(Krall et al., 2010 PLoS ONE e12859 and Canales et al., 2015 Brit JMedicine Med Res 5:1198-1212). Consequently, inhibition of TRPC6 may beuseful in the treatment of chronic kidney diseases. These findings notonly suggest that TRPC6 normally functions to maintain proper kidneyfunction, but also implicates TRPC6 as a specific cause of at leastcertain cases of FSGS. Based on the likely role of TRPC6 in kidneyfunction, TRPC6 inhibitor compounds can be used in treating orameliorating chronic kidney diseases or conditions caused (in whole orin part) by TRPC6 dysfunction. Additionally, TRPC6 inhibitor compoundscan be used in treating or ameliorating symptoms of kidney diseases(e.g., hypertension, proteinuria, etc.), regardless of the cause of thedisease.

TRPC6 is expressed in the myometrium and placenta during pregnancy (Kuet al., 2006 J Soc Gynecol Investig 13:217-225; Clarson et al., 2003 JPhysiol 550:515-528). As such TRPC6 may contribute to maintaining propermyogenic tone in the placenta and/or in maintaining proper fetal andmaternal blood pressure during pregnancy.

Recent evidence has emerged implicating TRPC6 in certain forms ofcancer. Several groups have established that TRPC6 expression iselevated in cells taken from patients with gliobastoma multiforme, themost frequent and incurable type of brain cancer (Chigurupati, et al.,2010 Cancer Res, 70:418-427; Ding et al., 2010 J Natl Cancer Inst.102:1052-1068).

Similarly, Ding et al. found elevated levels of TRPC6 in human gliomacells, and inhibition of TRPC6 pharmacologically or with adominant-negative mutant suppressed cell growth in vitro. In twoxenograft models of human gliomas, lentiviral-mediated expression ofdominant-negative TRPC6 in the tumor cells prior subcutaneous orintracranial implantation reduced tumor volume when compared to controls(Ding et al., J. Natl. Cancer Inst. 2010, 102, 1052-1068). Increasedlevels of TRPC6 was also found to be associated with cervical cancer(Wan et al, 2012 Onco Targets Ther 5:171-176), breast cancer(Dhennin-Duthille et al., 2011 Cell Physiol Biochem 28:813-822), renalcell carcinoma (Song et al, 2013 Mol Biol Rep 40:5115-5122), head andneck squamous cell carcinoma (de Quiros, et al. 2013 BMC Cancer13:116-127), and esophageal squamous cell carcinoma (Zhang et al., 2013Med Oncol 30:607), among others. In hepatocellular carcinoma cells, itwas demonstrated that doxorubicin, hypoxia, and ionizing radiationincreased TRPC6 mRNA expression, and that TRPC6 is found at higherlevels in tumor tissues than in the non-involved tissues. Elevated TRPC6was associated with drug resistance which was diminished by TRPC6 RNAsilencing in vitro. Lentiviral delivery of TRPC6 specific short hairpinRNA into Huh7 tumor cells prior to implantation in a mouse subcutaneousxenograft model reduced tumor growth and sensitized the tumors todoxorubicin (Wen et al., 2016 Sci Rep 6:23269). These findings suggestthat TRPC6 may be a promising therapeutic target for cancer treatment.

Liver diseases including non-alcoholic steatohepatitis may be treated byreducing TRPC6 activity. Hypoxia increased TRPC6 expression in a humanhepatic stellate cell line when compared to normoxic conditions. Usingthese cells, TRPC6 RNA silencing down-regulated transcripts for alphasmooth muscle actin and collagen 1A1, both of which are associated withfibrosis, in response to hypoxia Oyer et al., 2015 Exp Cell Res336:66-75).

Inhibition of TRPC6 may provide benefit to patients with Duchennemuscular dystrophy (DMD). In the mdx/utrn^(+/−) model of DMD usingisolated cardiomyoctes, TRPC6 deficiency restored the stress-stimulatedcontractility force and calcium transient response to normal whencompared with mice possessing the wild-type TRPC6 gene, suggesting thatTRPC6 inhibition will preserve cardiac function in DMD patients (Seo etal., 2014 Circ Res 114:823-32).

Fibrotic disorders may be treated with TRPC6 inhibitors. Overexpressionof TRPC6 induced myofibroblast activation while deletion of TRPC6reduced transforming growth factor beta-induced myofibroblasttransformation. Furthermore, TRPC6 deficient mice demonstrated reduceddermal and cardiac wound healing (Davis et al., 2012 Dev Cell23:705-15).

TRPC6 inhibitors may be useful for the treatment of pain. Spinaldelivery of TRPC6 antisense oligonucleotides reduced hyperalgesiainduced by mechanical, hypotonic, and thermal stimuli in preclinicalpain models (Alessandri-Haber et al., 2009 J Neurosci 29:6217-28).

Modulating a function of TRPC6 provides a means for modulating calciumhomeostasis, sodium homeostasis, intracellular calcium levels, membranepolarization (resting membrane potential), and/or cation levels in acell. Compounds that can modulate one or more TRPC6 functions are usefulin many aspects including, but not limited to, maintaining calciumhomeostasis; maintaining sodium homeostasis; modulating intracellularcalcium levels; modulating membrane polarization (membrane potential);modulating cation levels; and/or treating or preventing diseases,disorders, or conditions associated with calcium homeostasis, sodiumhomeostasis, calcium or sodium dyshomeostasis, or membranepolarization/hyperpolarization (including hypo and hyperexcitability),and/or treating or preventing diseases, disorders, or conditionsassociated with regulation or dysregulation of TRPC6 expression orfunction.

There is a need for highly selective TRPC6 antagonists for treatingdiseases or disorders that can be alleviated by modulating TRPC6.

BRIEF SUMMARY OF THE INVENTION

The present invention provides novel compounds that modulate TRPC6 andthus are useful for treating a variety of diseases and disorders thatcan be alleviated by modulating TRPC6 including hypertension,preeclampsia, restenosis, a cardiac or respiratory condition, renaldisease, liver disease, muscular dystrophy, fibrotic disorders, pain,ischemia or ischemic reperfusion injury, and cancer. This invention alsorelates to pharmaceutical compositions comprising these compounds,methods of using these compounds in the treatment of various diseasesand disorders, processes for preparing these compounds and intermediatesuseful in these processes.

In one embodiment (embodiment one), the invention relates to a compoundof formula (I),

wherein

L is absent or is methylene or ethylene;

Y is CH or N;

A is CH or N;

R¹ is selected from the group consisting of:

-   -   C₁₋₆alkyl optionally substituted with 1 to 3 groups        independently selected from the group consisting of halo,        C₃₋₆cycloalkyl and OC₃₋₆cycloalkyl;

phenyl optionally substituted with 1 to 3 groups independently selectedfrom the group consisting of CF₃, halo, C₃₋₆cycloalkyl, OC₃₋₆cycloalkyl,OC₁₋₆alkyl optionally substituted with one to three halo; and

-   -   C₃₋₆cycloalkyl optionally substituted with 1 to 3 groups        independently selected from the group consisting of halo and        C₁₋₆alkyl optionally substituted with 1 to 3 halo;

R² is selected from the group consisting of H, C₁₋₆alkyl, OCF₃,C₃₋₆cycloalkyl, OC₁₋₆alkyl, OC₃₋₆cycloalkyl;

R³ is selected from the group consisting of H, C₁₋₆alkyl,C₃₋₆cycloalkyl, OC₃₋₆cycloalkyl; wherein each of the C₁₋₆alkyl,C₃₋₆cycloalkyl, OC₃₋₆cycloalkyl of the R³ group may be optionallysubstituted with one to three groups each independently selected fromthe group consisting of halo, OH, OC₁₋₆alkyl, SC₁₋₆alkyl, N(C₁₋₆alky)₂;and wherein one to three carbon atoms of the C₁₋₆alkyl of the R³ groupmay optionally be replaced one or two moieties selected from the groupconsisting of NH, N(C₁₋₆alkyl), O, and S;

R⁴ and R⁵ are each independently selected from the group consisting of Hor C₁₋₆alkyl;

R³ and R⁴ can together with the atom to which they are attached join toform a 3 to 9-membered carbocyclyl ring which optionally may contain oneto three heteroatoms selected from the group consisting of N, O, and S;or

R³ and R⁵ can together form a 3 to 9-membered bicyclic ring whichoptionally may contain one to three heteroatoms selected from the groupconsisting of N, O, and S;

R⁶ is selected from the group consisting of H, C₁₋₆alkyl, CN, CF₃, OCF₃,C₃₋₆cycloalkyl, OC₁₋₆alkyl, and OC₃₋₆cycloalkyl;

R⁷ is selected from the group consisting of H and OC₁₋₆alkyl;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment two), the invention relates to acompound according to the first embodiment above, wherein

R¹ is selected from the group consisting of:

-   -   C₁₋₆alkyl optionally substituted with 1 to 3 groups        independently selected from the group consisting of halo,        C₃₋₆cycloalkyl;    -   phenyl optionally substituted with 1 to 3 groups independently        selected from the group consisting of CF₃, halo,        OC₃₋₆cycloalkyl, and OC₁₋₆alkyl optionally substituted with one        to three halo; and    -   C₃₋₆cycloalkyl optionally substituted with 1 to 3 halo groups;

R² is OC₁₋₆alkyl;

R³ is selected from the group consisting of H, C₁₋₆alkyl optionallysubstituted with OH or OC₁₋₆alkyl,

R⁴ is H;

R⁵ is H;

R³ and R⁴ can together with the atom to which they are attached join toform a 3 to 9-membered carbocyclyl ring which optionally may contain oneto three heteroatoms selected from the group consisting of N and O; or

R³ and R⁵ can together form a 3 to 9-membered bicyclic which optionallymay contain one to three heteroatoms selected from the group consistingof N and O;

R⁶ is selected from the group consisting of H, C₁₋₆alkyl, OC₁₋₆alkyl,and OC₃₋₆cycloalkyl,

R⁷ is selected from the group consisting of H and OC₁₋₆alkyl;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment three), the invention relates to acompound according to embodiment one or two above, wherein

A is CH and Y is N; or

A is CH and Y is CH; or

A is N and Y is CH;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment four), the invention relates to acompound according to any one of embodiments one to three above, wherein

R¹ is selected from the group consisting phenyl optionally substitutedwith a group selected from the group consisting of CF₃, OCF₃, halo,OC₃₋₆cycloalkyl, and OC₁₋₆alkyl optionally substituted with one to threehalo; and,

R² is OC₁₋₆alkyl;

R³ is selected from the group consisting of H, C₁₋₆alkyl optionallysubstituted with OH or OC₁₋₆alkyl;

R⁴ is H;

R⁵ is H;

R³ and R⁴ can together with the atom to which they are attached join toform a 3 to 9-membered carbocyclyl ring which optionally may contain oneto three heteroatoms selected from the group consisting of N, O; or

R³ and R⁵ can together form a 3 to 9-membered bicyclic which optionallymay contain one to three heteroatoms selected from the group consistingof N and O;

R⁶ is selected from the group consisting of H, C₁₋₆alkyl, OC₁₋₆alkyl,and OC₃₋₆cycloalkyl;

R⁷ is selected from the group consisting of H and OC₁₋₆alkyl;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment five), the invention relates to acompound according to any one of embodiments one to four above, wherein

R¹ is selected from the group consisting phenyl optionally substitutedwith a group selected from the group consisting of CF₃, OCF₃, F, andmethoxy;

R² is selected from the group consisting of methoxy or ethoxy;

R³ is selected from the group consisting of H, 2-hydroxymethyl,methoxymethyl, 1-hydroxyethyl;

R⁴ is H;

R⁵ is H;

or

R³ is ethyl, and R³ and R⁴ join to form a spirocyclic ring;

or

R³ is ethyl or methoxymethyl, and R³ and R⁵ join to form a bicyclicring;

R⁶ is selected from the group consisting of H, methyl, methoxy, ethoxy,propoxy, and cyclylpropyloxy;

R⁷ is selected from the group consisting of H and methoxy;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment six), the invention relates to acompound according to any one of embodiments one to five above, wherein

R¹ together with L represent a group selected from the group consistingof phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl,4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-difluoromethoxyphenyl4-cyclopropyloxyphenyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl,2-fluorobenzyl, and phenylethyl;

R² is methoxy or ethoxy;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment seven), the invention relates to acompound according to any one of embodiments one to six above, wherein

Y is CH and A is N;

R¹ together with L represent a group selected from the group consistingof phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl,4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-difluoromethoxyphenyl4-cyclopropyloxyphenyl, benzyl, 2-fluorobenzyl, and phenylethyl;

R² is methoxy or ethoxy;

R³, R⁴ and R⁵ are each H;

R⁶ is H, methyl, methoxy or ethoxy;

R⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment eight), the invention relates to acompound according to any one of embodiments one to six above, wherein

Y is CH and A is CH;

R¹ together with L represent a group selected from the group consistingof phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl,4-trifluoromethylphenyl, cyclopentyl, cyclohexyl, benzyl,2-fluorobenzyl, phenylethyl;

R² is methoxy or ethoxy;

R³, R⁴ and R⁵ are each H;

R⁶ is H, methyl, methoxy, or ethoxy;

R⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment nine), the invention relates to acompound according to any one of embodiments one to five above, wherein

Y is N and A is CH;

R¹ together with L represent a group selected from the group consistingof phenyl, and 4-fluorophenyl;

R² is methoxy;

R³ is selected from the group consisting of H, 2-hydroxymethyl, andhydroxyethyl,

R⁴ is H;

R⁵ is H;

R³ and R⁴ may join to form a spirocyclic ring;

or

R³ and R⁵ may join to form a bicyclic ring;

R⁶ is selected from the group consisting of H and methoxy;

R⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment ten), the invention relates to acompound according to any one of embodiments one to four above, wherein

R¹ is C₁₋₆alkyl optionally substituted with 1 to 3 groups independentlyselected from the group consisting of halo and C₃₋₆cycloalkyl;

R² is OC₁₋₆alkyl;

R³, R⁴ and R⁵ are each H;

R⁶ is selected from the group consisting of H, C₁₋₆alkyl, andOC₁₋₆alkyl;

R⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment eleven), the invention relates to acompound according to any one of embodiments one to four and ten above,wherein

R¹ together with L represent a group selected from the group consistingethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl,2,2-dimethylpropyl, 1-methylcyclopropylmethyl,1-fluoromethylcyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl,cyclopentyl, cyclohexyl, 2,2-difluorocyclobutylmethyl,3,3-difluorocyclobutylmethyl, 3-(trifluoromethyl)cyclobutylmethyl, and3,3,3-trifluoro-2-methyl-propyl;

R² is methoxy;

R³, R⁴ and R⁵ are each H;

R⁶ is selected from the group consisting of H, methyl, and methoxy;

R⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment twelve), the invention relates to acompound according to any one of embodiments one to four, ten and elevenabove, wherein

Y is CH and A is N;

R¹ together with L represent a group selected from the group consistingpropyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl,2,2-dimethylpropyl, 1-cyclopropylethyl, 2-cyclopropylethyl, andcyclohexyl;

R² is methoxy;

R³, R⁴ and R⁵ are each H;

R⁶ is selected from the group consisting of H, methyl, and methoxy;

R⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment thirteen), the invention relates to acompound according to any one of embodiments one to four, ten and elevenabove, wherein

Y is CH and A is CH;

R¹ together with L represent a group selected from the group consistingethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl,2,2-dimethylpropyl, 1-methylcyclopropylmethyl, 1-fluoromethylcyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl,cyclopentyl, cyclohexyl, 2,2-difluorocyclobutylmethyl,3,3-difluorocyclobutylmethyl, 3-(trifluoromethyl)cyclobutylmethyl, and3,3,3-trifluoro-2-methyl-propyl;

R² is methoxy;

R³, R⁴ and R⁵ are each H;

R⁶ is selected from the group consisting of H, methyl, and methoxy;

R⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment fourteen), the invention relates to acompound according to embodiment one above, wherein

R³ and R⁴ together with the atom to which they are attached join to forma 3-membered carbocyclyl ring;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment fifteen), the invention relates to acompound according to embodiment one above, wherein

R³ and R⁵ together form a 3 to 9-membered bicyclic ring which optionallymay contain one to two heteroatoms independently selected from the groupconsisting of N and O, and

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment sixteen), the invention relates to acompound according to embodiment one above, wherein

Y is C;

A is N;

R² is OCH₃; and

R³, R⁴, R⁵ and R⁷ are each H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment seventeen), the invention relates to acompound according to embodiment one or sixteen above, wherein

L is absent;

R¹ is phenyl optionally substituted with 1 to 3 groups independentlyselected from the group consisting of CF₃, halo, C₃₋₆cycloalkyl,OC₃₋₆cycloalkyl, OC₁₋₆alkyl optionally substituted with one to threehalo; and

R⁶ is H; or OCH₃;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment eighteen, the invention relates to acompound according to any one of embodiments one or sixteen above,wherein

R¹ is selected from the group consisting of phenyl optionallysubstituted with 1 to 3 groups independently selected from the groupconsisting of CF₃, halo, OC₃₋₆cycloalkyl, and OC₁₋₆alkyl optionallysubstituted with one to three halo;

R² is OCH₃ or OCH2CH₃;

R³, R⁴, R⁵, R⁶, and R⁷ are each H; and

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment nineteen), the invention relates to acompound according to any one of embodiments one or sixteen above,wherein

R¹ is selected from the group consisting of phenyl optionallysubstituted with 1 to 3 groups independently selected from the groupconsisting of CF₃, halo, OC₃₋₆cycloalkyl, and OC₁₋₆alkyl optionallysubstituted with one to three halo;

R² is OCH₃ of OCH2CH₃;

R³, R⁴, R⁵ and R⁷ are each H;

R⁶ is CH₃ or OCH₃;

Y is CH; and

A is N;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment twenty), the invention relates to anyone of embodiments one or sixteen to nineteen, wherein L is absent;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment twentyone), the invention relates to acompound according to embodiment one above, wherein the compound isselected from the group consisting of any one of compounds 1-95 in Table1, or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment twentytwo), the invention relates to apharmaceutical composition comprising any one of the compounds accordingto embodiments one to twentyone above, or a pharmaceutically acceptablesalt thereof, and optionally a pharmaceutically acceptable excipient.

In another embodiment (embodiment twentythree), the invention relates toa method of treating a disease or disorder that can be alleviated TRPC6inhibition comprising administering a therapeutically effective amountof any one of the compounds according to any one of embodiments one totwentyone above, or a pharmaceutically acceptable salt thereof, to apatient in need thereof.

In another embodiment (embodiment twentyfour), the invention relates toa method according to embodiment twentythree, wherein the disease ordisorder is selected from the group consisting of cardiac hypertrophy,ischemia, ischemic reperfusion injury, hypertension, pulmonary arterialhypertension, idiopathic pulmonary arterial hypertension, restenosis,chronic obstructive pulmonary disease, cystic fibrosis, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), trauma induced brain disorders, asthma, chronicobstructive pulmonary disease, rheumatoid arthritis, osteoarthritis,inflammatory bowel disease, multiple sclerosis, muscular dystrophy,Duchenne muscular dystrophy, preeclampsia and pregnancy-inducedhypertension, non-alcoholic steatohepatitis, minimal change disease,focal segmental glomerulosclerosis (FSGS), nephrotic syndrome, diabeticnephropathy or diabetic kidney disease (DKD), renal insufficiency, endstage renal disease, ischemia or an ischemic reperfusion injury, cancer,IPF (idiopathic pulmonary fibrosis), ARDS (acute respiratory diseasesyndrome), emphysema and diabetes.

DETAILED DESCRIPTION OF THE INVENTION

Table 1 shows the compounds of the invention which can be made by thesynthetic schemes and the examples shown in the Synthetic Examplessection below, and known methods in the art.

TABLE 1 Cpd No. Structure Compound Name 1

[4-(6-Amino-4-methoxy-pyridin-3-yl)- piperazin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]- methanone 2

(6-Amino-4-methyl-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(4-fluoro-phenoxy)-4-methoxy- pyridin-2-yl]-methanone 3

(6-Amino-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(4-methoxy-5- phenoxy-pyridin-2-yl)-methanone 4

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(4-fluoro-phenoxy)-4-methoxy- pyridin-2-yl]-methanone 5

[4-(6-Amino-4-methoxy-pyridin-3-yl)- piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 6

[4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl]-[5-(4-isopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]- methanone 7

[(R)-4-(6-Amino-4-methyl-pyridin-3- yl)-2-hydroxymethyl-piperazin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy- pyridin-2-yl]-methanone 8

[7-(6-Amino-4-methoxy-pyridin-3-yl)- 4,7-diaza-spiro[2.5]oct-4-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)- methanone 9

[7-(6-Amino-4-methoxy-pyridin-3-yl)-4,7-diaza-spiro[2.5]oct-4-yl]-[5-(4- fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone 10

(6-Amino-4-methyl-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl)- methanone 11

[4-(6-Amino-5-methoxy-pyridazin-3- yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]- methanone 12

[4-(6-Amino-pyridin-3-yl)-piperazin- 1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone 13

[4-(6-Amino-pyridin-3-yl)-piperazin- 1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone 14

(6-Amino-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(4-fluoro- phenoxy)-4-methoxy-pyridin-2-yl]-methanone 15

[4-(6-Amino-pyridin-3-yl)-piperazin- 1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 16

[4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 17

[4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone 18

[(R)-4-(6-Amino-4-methyl-pyridin-3- yl)-2-hydroxymethyl-piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)- methanone 19

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(2-fluoro-benzyloxy)-4-methoxy- pyridin-2-yl]-methanone 20

[(R)-4-(6-Amino-pyridin-3-yl)-2- hydroxymethyl-piperazin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin- 2-yl]-methanone 21

[4-(6-Amino-5-methoxy-pyridazin-3- yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 22

(6-Amino-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]- methanone 23

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl)- methanone 24

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[4-methoxy-5-(4-trifluoromethyl- phenoxy)-pyridin-2-yl]-methanone 25

[4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl]-(5-cyclobutylmethoxy-4-methoxy-pyridin-2-yl)-methanone 26

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[4-methoxy-5-(1-methyl- cyclopropylmethoxy)-pyridin-2-yl]- methanone 27

[(R)-4-(6-Amino-4-methoxy-pyridin- 3-yl)-2-methoxymethyl-piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2- yl)-methanone 28

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[4-methoxy-5-(4-methoxy-phenoxy)- pyridin-2-yl]-methanone 29

[4-(6-Amino-4-methyl-pyridazin-3- yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]- methanone 30

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-cyclohexyloxy-4-methoxy-pyridin- 2-yl)-methanone 31

[4-(6-Amino-4-methyl-pyridazin-3- yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 32

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(4-fluoro-benzyloxy)-4-methoxy- pyridin-2-yl]-methanone 33

[4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2- yl]-methanone 34

[4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl]-[5-(4-chloro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone 35

(6-Amino-4-methoxy-3,4,5,6′- tetrahydro-2'H-[3,4']bipyridinyl-1′-yl)-(5-cyclopentyloxy-4-methoxy- pyridin-2-yl)-methanone 36

[4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl]-(5-isobutoxy-4-methoxy-pyridin-2-yl)-methanone 37

(6-Amino-4-methoxy-3′,4′,5′,6'- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-cyclopropylmethoxy-4-methoxy- pyridin-2-yl)-methanone 38

[3-(6-Amino-4-methoxy-pyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2- yl]-methanone 39

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-isobutoxy-4-methoxy-pyridin-2-yl)- methanone 40

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-cyclopropoxy-phenoxy)-4- methoxy-pyridin-2-yl]-methanone 41

[4-(6-Amino-pyridazin-3-yl)-piperidin- 1-yl]-[5-(4-fluoro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanone 42

[(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]- [5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone 43

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-benzyloxy-4-methoxy-pyridin-2-yl)- methanone 44

[4-(6-Amino-pyridazin-3-yl)-piperidin- 1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone 45

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(3,3-difluoro-cyclobutylmethoxy)-4- methoxy-pyridin-2-yl]-methanone46

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(4-methoxy-5-propoxy-pyridin-2-yl)- methanone 47

[4-(6-Amino-4-methoxy-pyridazin-3- yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 48

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(2-cyclopropyl-ethoxy)-4-methoxy- pyridin-2-yl]-methanone 49

[4-(6-Amino-4-methoxy-pyridazin-3- yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]- methanone 50

(1R)-1-[(2R)-4-(6-amino-4- methoxypyridin-3-yl)-1-(5- phenoxypyridine-2-carbonyl)piperazin-2-yl]ethan-1-ol 51

[3-(6-Amino-4-methoxy-pyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-(4- methoxy-5-phenoxy-pyridin-2-yl)-methanone 52

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(4-methoxy-5-phenethyloxy-pyridin-2- yl)-methanone 53

(6-Amino-4-rnethoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)- (5-cyclobutylmethoxy-4-methoxy-pyridin-2-yl)-methanone 54

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-difluoromethoxy-phenoxy)- 4-methoxy-pyridin-2-yl]-methanone55

[(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-methoxymethyl-piperazin-1-yl]- [5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone 56

[4-(6-Amino-4-methoxy-pyridazin-3- yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]- methanone 57

[4-(6-Amino-pyridazin-3-yl)-piperidin- 1-yl]-[5-(2-fluoro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanone 58

(1S)-1-[(2R)-4-(6-amino-4- methoxypyridin-3-yl)-1-(5- phenoxypyridine-2-carbonyl)piperazin-2-yl]ethan-1-ol 59

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(2,2-dimethyl-propoxy)-4-methoxy- pyridin-2-yl]-methanone 60

[4-(6-Amino-5-methoxy-pyridazin-3- yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]- methanone 61

[4-(6-Amino-4-methoxy-pyridin-3-yl)- piperazin-1-yl]-(5-cyclopropylmethoxy-4-methoxy- pyridin-2-yl)-methanone 62

[4-(6-Amino-pyridazin-3-yl)-piperidin- 1-yl]-(5-cyclohexyloxy-4-methoxy-pyridin-2-yl)-methanone 63

[(S)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]- [5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone 64

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(1-fluoromethyl- cyclopropylmethoxy)-4-methoxy-pyridin-2-yl]-methanone 65

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-ethoxy-4-methoxy-pyridin-2-yl)- methanone 66

[4-(6-Amino-4-methoxy-pyridazin-3- yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]- methanone 67

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(2-cyclopropyl-ethoxy)-4- methoxy-pyridin-2-yl]-methanone 68

[7-(6-Amino-4-methoxy-pyridin-3-yl)-3-oxa-9-aza-bicyclo[3.3.1]non-9-yl]- (4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 69

[(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]- (4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 70

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-((S)-1-cyclopropyl-ethoxy)-4- methoxy-pyridin-2-yl]-methanone 71

[(S)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]- (4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 72

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-isopropoxy-4-methoxy-pyridin-2- yl)-methanone 73

[4-(6-Amino-pyridazin-3-yl)-piperidin- 1-yl]-(4-methoxy-5-phenethyloxy-pyridin-2-yl)-methanone 74

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(2,2-dimethyl-propoxy)-4- methoxy-pyridin-2-yl]-methanone 75

[4-(6-Amino-pyridazin-3-yl)-piperidin- 1-yl]-[4-methoxy-5-(1-methyl-cyclopropylmethoxy)-pyridin-2-yl]- methanone 76

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-propoxy-pyridin-2- yl)-methanone 77

(6-Amino-4-methoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-((R)-1-cyclopropyl-ethoxy)-4- methoxy-pyridin-2-yl]-methanone 78

[4-(6-Amino-4-methyl-pyridazin-3-yl)- piperidin-1-yl]-(5-cyclopropylmethoxy-4-methoxy- pyridin-2-yl)-methanone 79

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-((S)-1-cyclopropyl-ethoxy)-4- methoxy-pyridin-2-yl]-methanone80

[4-(6-Amino-pyridazin-3-yl)-piperidin- 1-yl]-[4-methoxy-5-(4-trifluoromethoxy-phenoxy)-pyridin-2- yl]-methanone 81

[(R)-4-(6-Amino-pyridin-3-yl)-2- hydroxymethyl-piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)- methanone 82

[(R)-4-(6-Amino-pyridin-3-yl)-2- hydroxymethyl-piperazin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)- pyridin-2-yl]-methanone 83

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(phenoxy)-4-ethoxy-pyridin-2- yl]-methanone 84

(6-Amino-4-cyclopropoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(phenoxy)-4-methoxy-pyridin-2-yl]- methanone 85

[4-(6-Amino-4-ethoxy-pyridazin-3-yl)- piperidin-1-yl]-[4-methoxy-5-(phenoxy)-pyridin-2-yl]-methanone 86

(6-Amino-4-propoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(phenoxy)-4-methoxy-pyridin-2-yl]- methanone 87

(6-Amino-4-ethoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(4-trifluoromethyl-phenoxy)-4- methoxy-pyridin-2-yl]-methanone 88

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-ethoxy- pyridin-2-yl]-methanone 89

[3-(6-Amino-pyridazin-3-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-[4-ethoxy-5-(4- fluoro-phenoxy)-pyridin-2-yl]-methanone 90

6-{1-{4-Methoxy-5-[4- (trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5- methylpyridazin-3-amine 91

5-Methoxy-6-(1-{5-[4- (trifluoromethyl)-phenoxy]-pyridine-2-carbonyl}piperidin-4-yl)-pyridazin-3- amine 92

4-Methoxy-5-[1-(4-methoxy-5-{[trans- 3-(trifluoromethyl)cyclobutyl]-methoxy}pyridine-2-carbonyl)- piperidin-4-yl]pyridin-2-amine 93

4-Methoxy-5-[1-(4-methoxy-5-{[(cis- 3-(trifluoromethyl)-cyclobutyl]methoxy}-pyridine-2- carbonyl)piperidin-4-yl]pyridin-2- amine94

4-Methoxy-5-(1-{4-methoxy-5-[(2)- 3,3,3-trifluoro-2-methylpropoxy]-pyridine-2-carbonyl}piperidin-4- yl)pyridin-2-amine 95

5-{1-{5-[(2,2-Difluorocyclobutyl)- methoxy]-4-methoxy-pyridine-2-carbonyl}-piperidin-4-yl)-4- methoxypyridin-2-amine

In one embodiment, the invention relates to any of the compounds 1 to 95depicted in Table 1 above, and the pharmaceutically acceptable saltsthereof.

In another embodiment, the invention relates to any one of compounds 6,16, 17, 33, 34, 40, 41, 44, 54, 57, 80, 83 and 88 depicted in Table 1;and the pharmaceutically acceptable salts thereof.

In another embodiment, the invention relates to any one of compounds 29,31, 49, 56, 66, 85, 87, and 90 depicted in Table 1; and thepharmaceutically acceptable salts thereof.

General Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In generalin groups like HO, H₂N, (O)S, (O)₂S, NC (cyano), HOOC, F₃C or the like,the skilled artisan can see the radical attachment point(s) to themolecule from the free valences of the group itself. For combined groupscomprising two or more subgroups, the last named subgroup is the radicalattachment point, for example, the substituent “aryl-C₁₋₃-alkyl” meansan aryl group which is bound to a C₁₋₃-alkyl-group, the latter of whichis bound to the core or to the group to which the substituent isattached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk is may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc.) and racemates thereof aswell as mixtures in different proportions of the separate enantiomers,mixtures of diastereomers, or mixtures of any of the foregoing formswhere such isomers and enantiomers exist, as well as salts, includingpharmaceutically acceptable salts thereof and solvates thereof such asfor instance hydrates including solvates of the free compounds orsolvates of a salt of the compound.

Enantiomerically pure compounds of this invention or intermediates maybe prepared via asymmetric synthesis, for example by preparation andsubsequent separation of appropriate diastereomeric compounds orintermediates which can be separated by known methods (e.g. bychromatographic separation or crystallization) and/or by using chiralreagents, such as chiral starting materials, chiral catalysts or chiralauxiliaries.

Further, it is known to the person skilled in the art how to prepareenantiomerically pure compounds from the corresponding racemic mixtures,such as by chromatographic separation of the corresponding racemicmixtures on chiral stationary phases; or by resolution of a racemicmixture using an appropriate resolving agent, e.g. by means ofdiastereomeric salt formation of the racemic compound with opticallyactive acids or bases, subsequent resolution of the salts and release ofthe desired compound from the salt; or by derivatization of thecorresponding racemic compounds with optically active chiral auxiliaryreagents, subsequent diastereomer separation and removal of the chiralauxiliary group; or by kinetic resolution of a racemate (e.g. byenzymatic resolution); by enantioselective crystallization from aconglomerate of enantiomorphous crystals under suitable conditions; orby (fractional) crystallization from a suitable solvent in the presenceof an optically active chiral auxiliary.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio. As used herein,“pharmaceutically acceptable salt” refers to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like.

For example, such salts include salts from benzenesulfonic acid, benzoicacid, citric acid, ethanesulfonic acid, formic acid, fumaric acid,gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malicacid, malonic acid, mandelic acid, methanesulfonic acid,4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinicacid, sulfuric acid tartaric acid, and trifluoroacetic acid.

Further pharmaceutically acceptable salts can be formed with cationsfrom ammonia, L-arginine, calcium, 2,2′-iminobisethanol, L-lysine,magnesium, N-methyl-D-glucamine, potassium, sodium andtris(hydroxymethyl)-aminomethane.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts, formates) also comprise a part of theinvention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine

The term “C_(1-n)-alkyl”, wherein n is an integer selected from thegroup consisting of 2, 3, 4, 5 or 6, preferably 4 or 6, either alone orin combination with another radical denotes an acyclic, saturated,branched or linear hydrocarbon radical with 1 to n C atoms. For examplethe term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—, H₃C—CH₂—CH₂—,H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—,H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—, H₃C—CH₂—CH₂—CH(CH₃)—,H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—, H₃C—CH₂—C(CH₃)₂—,H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— and H₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer from 4 to n,either alone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Forexample the term C₃₋₇-cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

By the term “halo” added to an “alkyl”, “alkylene” or “cycloalkyl” group(saturated or unsaturated) is such an alkyl or cycloalkyl group whereinone or more hydrogen atoms are replaced by a halogen atom selected fromamong fluorine, chlorine or bromine, preferably fluorine and chlorine,particularly preferred is fluorine. Examples include: H₂FC—, HF₂C—,F₃C—.

Analogously, the term “halo” added to an aryl group (e.g., phenyl) meansthat one or more hydrogen atoms are replaced by a halogen atom selectedfrom among fluorine, chlorine or bromine, preferably fluorine andchlorine, particularly preferred is fluorine.

The term “carbocyclyl” as used either alone or in combination withanother radical, means a mono- bi- or tricyclic ring structureconsisting of 3 to 9 carbon atoms and optionally a heteroatom selectedfrom the group consisting of N, O, and S. The term “carbocyclyl” refersto fully saturated ring systems and encompasses fused, bridged andspirocyclic systems.

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

The present application provides compounds that can modulate TRPC6function. Methods employing these compounds are also provided. Certainembodiments provide a method of modulating a TRPC6 function in a cell oranimal comprising administering an effective amount of a compound thatinhibits a TRPC6 function, wherein the compound inhibits aTRPC6-mediated ion flux. Certain embodiments provide a method ofmodulating a TRPC6 function in a cell or animal comprising administeringan effective amount of a compound that inhibits a TRPC6 function,wherein the compound inhibits a TRPC6-mediated calcium influx. Certainembodiments provide a method of modulating a TRPC6 function in a cell oranimal comprising administering an effective amount of a compound thatinhibits a TRPC6 function, wherein the compound inhibits aTRPC6-mediated cytoskeletal reorganization or alteration in cellmorphology. Certain embodiments provide a method of modulating a TRPC6function in a cell comprising administering to the cell an effectiveamount of a compound that inhibits TRPC6 function, wherein the compoundinhibits outward current mediated by TRPC6. Certain embodiments providea method of modulating a TRPC6 function in a cell comprisingadministering to the cell an effective amount of a compound thatinhibits TRPC6 function, wherein the compound inhibits inward currentmediated by TRPC6. Certain embodiments provide a method of modulating aTRPC6 function in a cell comprising administering to the cell aneffective amount of a compound that inhibits TRPC6 function, wherein thecompound inhibits both the inward and outward currents mediated byTRPC6. Certain embodiments provide a method of modulating a TRPC6function in a cell comprising administering to the cell an effectiveamount of a compound that inhibits TRPC6 function, wherein the compoundinhibits TRPC6 mediated increases in intracellular calciumconcentration. Certain embodiments provide a method of modulating aTRPC6 function in a cell comprising administering to the cell aneffective amount of a compound that inhibits TRPC6 function, wherein thecompound inhibits alterations in cell morphology. Certain embodimentsalso provide a method of preventing or treating a disease or conditionrelated to TRPC6 function in a subject comprising administering to thesubject a therapeutically effective amount of a compound that inhibitsTRPC6 function, wherein the compound inhibits the inward currentmediated by TRPC6. Certain embodiments provide a method of preventing ortreating a disease or condition related to TRPC6 function in a subjectcomprising administering to the subject a therapeutically effectiveamount of a compound that inhibits TRPC6 function, wherein the compoundinhibits the outward current mediated by TRPC6. Certain embodiments alsoprovide a method of preventing or treating a disease or conditionrelated to TRPC6 function in a subject comprising administering to thesubject a therapeutically effective amount of a compound that inhibitsTRPC6 function, wherein the compound inhibits both the inward andoutward current mediated by TRPC6. Certain embodiments provide a methodof preventing or treating a disease or condition related to TRPC6function in a subject comprising administering to the subject atherapeutically effective amount of a compound that inhibits TRPC6function, wherein the compound inhibits the ion flux mediated by TRPC6.Note that inhibition of a particular current refers to the ability of acompound to inhibit that current (e.g., inward and/or outward) in eitheran in vitro or an in vivo assay. Inhibition of a particular current ineither an in vivo or an in vitro assay serves as a proxy for theparticular functional activity of the particular compound.

The present invention provides methods of treating a TRPC6 mediateddisorder in a subject, the method comprising administering an effectiveamount of a compound of the invention wherein each of the variablesabove are described herein, for example, in the detailed descriptionbelow.

The present invention further provides a method for treating a TRPC6mediated disorder in a subject, wherein the method comprisesadministering a composition comprising a compound of the invention and apharmaceutically acceptable excipient, diluent or carrier.

The present invention further provides a method for treating a TRPC6mediated disorder in a subject, wherein the method comprisesadministering a composition comprising a compound of the invention and apharmaceutically acceptable excipient, diluent or carrier, and the TRPC6mediated disorder is selected from the group consisting of cardiachypertrophy, ischemia, ischemic reperfusion injury, hypertension,pulmonary arterial hypertension, idiopathic pulmonary arterialhypertension, restenosis, chronic obstructive pulmonary disease, cysticfibrosis, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis (ALS), trauma induced braindisorders, asthma, chronic obstructive pulmonary disease, rheumatoidarthritis, osteoarthritis, inflammatory bowel disease, multiplesclerosis, muscular dystrophy, preeclampsia and pregnancy-inducedhypertension, non-alcoholic steatohepatitis, focal segmentalglomerulosclerosis, nephrotic syndrome, diabetic nephropathy or diabetickidney disease, renal insufficiency, end stage renal disease, ischemiaor an ischemic reperfusion injury, cancer, IPF (idiopathic pulmonaryfibrosis), ARDS (acute respiratory disease syndrome), emphysema anddiabetes.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof aswell as mixtures in different proportions of the separate enantiomers,mixtures of diastereomers, or mixtures of any of the foregoing formswhere such isomers and enantiomers exist, as well as salts, includingpharmaceutically acceptable salts thereof and solvates thereof such asfor instance hydrates including solvates of the free compounds orsolvates of a salt of the compound.

Some of the compounds in Table 1 can exist in more than one tautomericform. The invention includes methods for using all such tautomers.

The invention includes pharmaceutically acceptable derivatives ofcompounds of the invention. A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester, or any othercompound which, upon administration to a patient, is capable ofproviding (directly or indirectly) a compound useful for the invention,or a pharmacologically active metabolite or pharmacologically activeresidue thereof. A pharmacologically active metabolite shall beunderstood to mean any compound of the invention capable of beingmetabolized enzymatically or chemically. This includes, for example,hydroxylated or oxidized derivative compounds of the invention.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. For example,such salts include acetates, ascorbates, benzenesulfonates, benzoates,besylates, bicarbonates, bitartrates, bromides/hydrobromides, edetates,camsylates, carbonates, chlorides/hydrochlorides, citrates, edisylates,ethane disulfonates, estolates esylates, formates, fumarates,gluceptates, gluconates, glutamates, glycolates, glycollylarsnilates,hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates,iodides, isothionates, lactates, lactobionates, malates, maleates,mandelates, methanesulfonates, methylbromides, methylnitrates,methylsulfates, mucates, napsylates, nitrates, oxalates, pamoates,pantothenates, phenylacetates, phosphates/diphosphates,polygalacturonates, propionates, salicylates, stearates, subacetates,succinates, sulfamides, sulfates, tannates, tartrates, teoclates,toluenesulfonates, triethiodides, trifluoroacetates, ammonium,benzathines, chloroprocaines, cholines, diethanolamines,ethylenediamines, meglumines and procaines. Further pharmaceuticallyacceptable salts can be formed with cations from metals like aluminium,calcium, lithium, magnesium, potassium, sodium, zinc and the like. (Alsosee Pharmaceutical salts, Birge, S. M. et al., J. Pharm. Sci., (1977),66, 1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts) also comprise a part of the invention.

In addition, within the scope of the invention is use of prodrugs ofcompounds of the invention. Prodrugs include those compounds that, uponsimple chemical transformation, are modified to produce compounds of theinvention. Simple chemical transformations include hydrolysis, oxidationand reduction. Specifically, when a prodrug is administered to apatient, the prodrug may be transformed into a compound disclosedhereinabove, thereby imparting the desired pharmacological effect.

Compounds of the invention also include their isotopically-labelledforms. An isotopically-labelled form of an active agent of a combinationof the present invention is identical to said active agent but for thefact that one or more atoms of said active agent have been replaced byan atom or atoms having an atomic mass or mass number different from theatomic mass or mass number of said atom which is usually found innature. Examples of isotopes which are readily available commerciallyand which can be incorporated into an active agent of a combination ofthe present invention in accordance with well established procedures,include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, e.g., ²H, ³⁰H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, and ³⁶Cl, respectively. An active agent of a combination ofthe present invention, a prodrug thereof, or a pharmaceuticallyacceptable salt of either which contains one or more of theabove-mentioned isotopes and/or other isotopes of other atoms iscontemplated to be within the scope of the present invention.

The compounds of the invention are only those which are contemplated tobe “chemically stable” as will be appreciated by those skilled in theart. For example, a compound which would have a “dangling valency”, or a“carbanion” are not compounds contemplated by the inventive methodsdisclosed herein.

For all compounds disclosed herein above in this application, in theevent the nomenclature is in conflict with the structure, it shall beunderstood that the compound is defined by the structure.

LIST OF ABBREVIATIONS

-   -   AA Acetic Acid    -   ACN/MeCN Acetonitrile    -   aq. Aqueous    -   BEH Ethylene bridged hybrid column    -   BOC Tert-butyloxycarbonyl    -   ° C. Degree Celsius    -   CDI Di(imidazol-1-yl)methanone    -   CPhos-3G-Methansulfonato(2-dicyclohexylphosphino-2′,6′-palladacycle        bis(dimethylamino)-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-methane        sulfonate yl)palladium(II)    -   DCM Dichloromethane    -   DIPEA N.N-diisopropylethylamine    -   DMF N,N-dimethylformamide    -   DMA N,N-dimethylacetamide    -   DMSO Dimethylsulfoxide    -   DTAD Di-tert-butyl azodicarboxylate    -   EE Diethylether    -   eq Equivalent    -   ESI-MS Electrospray ionisation mass spectrometry    -   EtOH Ethanol    -   EtOAc/EE Ethyl acetate    -   h Hour    -   H₂ Hydrogen    -   H₃PO₄ Phosphoric acid    -   HATU N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium        hexafluorophosphate    -   HCl Hydrochloric acid    -   HPLC High performance liquid chromatography    -   MeOH Methanol    -   min Minute    -   MeI Iodomethane    -   mL Milliliter    -   MS Mass spectrum    -   NaH Sodium hydride    -   NaOH Sodium hydroxide    -   NMP N-methyl-2-pyrrolidinone    -   Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0)    -   Pd/C Palladium on carbon    -   PdCl2(dppf)CH₂Cl₂        [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)        dichloromethane    -   Pd(OH)₂ Palladium hydroxide    -   PE Petroleum ether    -   RP Reverse phase    -   rt or RT Room temperature (about 25° C.)    -   SFC Supercritical fluid chromatography    -   TBTU Benzotriazolyl tetramethyuronium tetrafluoroborate    -   TFA Trifluoroacetic acid    -   THF Tetrahydrofuran    -   TLC Thin-layer chromatography on SiO₂    -   Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene    -   Xphos 2^(nd) Gen.        Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)    -   TPP Triphenylphosphine

General Methods: Unless noted otherwise, all reactions are run at roomtemperature (about 25° C.), under inert atmosphere (e.g., Argon, N₂),and under anhydrous conditions. All compounds are characterized by atleast one of the following methods: ¹H NMR, HPLC, MS, HPLC-MS, ormelting point.

Typically, reaction progress is monitored by thin layer chromatography(TLC) or HPLC-MS. Intermediates and products are purified using at leastone of the following methods:

Flash chromatography on silica gel, Recrystallization, Super CriticalFluid (SCF) Chiral HPLC using a 3.0×25.0 cm RegisPack column, elutingwith an isocratic mixture of MeOH, isopropylamine (IPA), and supercritical carbon dioxide at 125 bar; 80 mL/min, and/or Reversed phaseHPLC using a C18 semi-preparative column eluting with a gradient of:

-   -   MeCN+0.1% TFA and H₂O+0.1% TFA,    -   MeCN+0.1% formic acid and H₂O+0.1% formic acid, or    -   MeCN and H₂O containing 2.5 mM NH₄HCO₃    -   MeCN and H₂O+0.1% TFA,    -   MeCN and H₂O+0.1% NH₃,    -   MeCN and H₂O and 0.1% TFA    -   MeCN and H₂O and 0.1% NH₃

Analytical Data

The reported mass spectrometry (MS) data is for observed mass (e.g.,[M+H]⁺). The HPLC method used to characterize the compounds of theinvention is described in Table 2.

TABLE 2 HPLC Methods Gradient Mobile Mobile Time Flow Method Phase APhase B (min) % A % B (mL/min.) Column A 0.1% 0.1% 0 95.0 5.0 0.8 BEHFormic Formic 1.0 5.0 95.0 2.5 × 50 Acid in Acid in 1.3 5.0 95.0 mmWater MeCN 1.4 95.0 5.0 C18, 1.7 1.7 95.0 5.0 μm particle diameter

This method is utilized throughout the remainder of the tables in thissection for the ESI-MS and retention time data.

If a different HPLC-MS is used, it is indicated in the text

Method 1

ESI+/− ion mode. Column: CSH C18 2.1×50 mm, 1.7 μm particle diameter.Gradient: 90% A to 100% B in 1.19 minutes hold at 100% B to 1.70minutes. Flow rate 0.8 mL/min. A=(95% water+5% acetonitrile+0.05% formicacid) B=(acetonitrile+0.05% formic acid).

Method 2

ESI+/− ion mode. Column: BEH 2.1×50 mm C18, 1.7 μm particle diameter.Gradient: 90% A to 100% B in 4.45 minutes hold at 100% B to 4.58minutes. Flow rate 0.8 mL/min. A=(95% water+5% acetonitrile+2.5 mMammonium bicarbonate) B=(acetonitrile).

Method 3

ESI+/− ion mode. Column: BEH 2.1×50 mm C18, 1.7 μm particle diameter.Gradient: 90% A to 95% B in 1.19 minutes hold at 95% B to 1.70 minutes.Flow rate 0.8 mL/min. A=(95% water+5% acetonitrile+2.5 mM ammoniumbicarbonate) B=(acetonitrile).

Method 4

ESI+/− ion mode. Colum: HSS T3 2.1×100 mm, 1.8 μm particule diametre.Gradient:100% A hold for 1.00 minute, 100% A to 95% B in 4.50 minuteshold at 100% B to 4.91 minutes. Flow rate 0.6 mL/min. A=(95% water+5%acetonitrile+0.05% formic acid) B=(acetonitrile+0.05% formic acid).

Method 5

ESI+/− ion mode. Column: CSH C18 2.1×50 mm, 1.7 μm particle diameter:Gradient:90% A to 100% B in 4.45 minutes hold at 100% B to 4.58 minutes.Flow rate 0.8 mL/min. A=(95% water+5% acetonitrile+0.05% formic acid)B=(acetonitrile+0.05% formic acid).

Method 6

ESI+/− ion mode. Colum: HSS T3 2.1×100 mm, 1.8 μm particule diametre.Gradient: 95% A to 100% B in 3.65 minutes, hold at 100% B to 4.95minutes. Flow rate 0.6 mL/min. Column temperature 60 degrees Celsius.A=(95% water+5% acetonitrile+0.05% formic acid) B=(acetonitrile+0.05%formic acid).

Method 7 (column temperature 60° C.) Gradient Mobile Mobile Time FlowPhase A Phase B (min) % A % B (mL/min.) Column 0.1% TFA ACN 0 97.0 3.02.2 Sun fire in water 0.2 97.0 3.0 2.2 C18_3.0 × 1.2 0.0 100.0 2.2 30mm, 1.25 0.0 100.0 3.0 2.5 μm 1.4 0.0 100.0 3.0 particle diameter,

Method 8 (column temperature 40° C.) Gradient Mobile Mobile Time FlowPhase A Phase B (min) % A % B (mL/min.) Column Super- EtOH 20 0 60 404.0 CHIRAL ART ® critical mM NH₃ 10 60 40 Cellulose SC_4.6 × carbon 250mm_5 μm dioxide particle diameter

Method 9 Gradient Mobile Mobile Time Flow Phase A Phase B (min) % A % B(mL/min.) Column 0.1% TFA ACN 0 95.0 5.0 1.5 Sun fire C18_3.0 × in water0.08% 1.3 0.0 100.0 30 mm, 2.5 μm TFA 1.5 0.0 100.0 particle diameter1.6 95.0 5.0

Method 10 (column temperature 60° C.) Gradient Mobile Mobile Time FlowPhase A Phase B (min) % A % B (mL/min.) Column 0.1% TFA ACN 0 97.0 3.02.2 Zorbax Stable in Water 0.2 97.0 3.0 2.2 Bond C18_3.0 × 1.2 0.0 100.02.2 30 mm, 1.25 0.0 100.0 3.0 1.8 μm, 1.4 0.0 100.0 3.0 particlediameter

Method 11 Mobile Mobile Gradient Flow Phase Phase Time (mL/ A B (min) %A % B min) Column T° 0.1% ACN 0 97.0 3.0 2.2 XBridge 60° C. NH₃ in 0.297.0 3.0 2.2 C18_3.0 × water 1.2 0.0 100.0 2.2 30 mm, 1.25 0.0 100.0 3.02.5 μm 1.4 0.0 100.0 3.0 particle diameter

Method 12 Mobile Mobile Gradient Flow Phase Phase Time (mL/ A B (min) %A % B min) Column T° 0.1% ACN 0 99.0 1.0 1.5 Sun fire 60° C. TFA in 0.0299.0 1.0 1.5 C18_2.1 × water 1.00 0.0 100.0 1.5 30 mm, 1.10 0.0 100.01.5 2.5 μm particle diameter

Method 13 Mobile Mobile Gradient Phase Phase Time Flow A B (min) % A % B(mL/min) Column T° 0.1% ACN 0 95.0 5.0 1.5 XBridge 60° C. NH₃ in 1.3 0.0100.0 1.5 C18_3.0 × 30 water 1.5 0.0 100.0 1.5 mm, 2.5 μm 1.6 95 5.0 1.5particle diameter

Method 14 Mobile Mobile Gradient Flow Phase Phase Time (mL/ A B (min) %A % B min) Column T° 0.5% 0.5% 0 95.0 5.0 1.2 Halo 15° C. H₃PO₄ H₃PO₄ 195.0 5.0 1.2 C18_4.6 in water in ACN 4 70.0 30.0 1.2 mm × 5 62.5 37.51.2 15 cm, 7.5 61 39 1.2 2.7 μm 10 2 98 1.2 particle 12 2 98 1.2diameter

Synthetic Examples

The examples which follow are illustrative and, as recognized by oneskilled in the art, particular reagents or conditions could be modifiedas needed for individual compounds without undue experimentation.

The compounds of the invention may be prepared by the general methodsand examples presented below and methods known to those of ordinaryskill in the art. Optimum reaction conditions and reaction times mayvary depending on the particular reactants used. Unless otherwisespecified, solvents, temperatures, pressures, and other reactionconditions may be readily selected by one of ordinary skill in the art.Specific procedures are provided in the Synthetic Examples section.Intermediates used in the syntheses below are either commerciallyavailable or easily prepared by methods known to those skilled in theart. Reaction progress may be monitored by conventional methods such asthin layer chromatography (TLC) or high pressure liquidchromatography-mass spec (HPLC-MS). Intermediates and products may bepurified by methods known in the art, including column chromatography,HPLC, preparative TLC or recrystallization.

General Synthetic Procedure

The compounds of the invention are generally prepared by reacting acarboxylic acid intermediate of formula INT-1 with an amine intermediateof formula INT-2 under appropriate conditions as depicted below inScheme 1.

Intermediates INT-1 and INT-2 are known in the art or can be prepared bythe methods described below. The groups/terms R¹ to R⁷, A, Y and L areas defined above for the compound of formula (I).

Synthesis of Intermediates

4-[6-(2,5-Dimethyl-pyrrol-1-yl)-4-methoxy-pvridin-3-yl]-piperazine-1-carboxylicacid tert-butyl ester

To piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 5.37 mmol) and5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridine (1.5 g, 5.37mmol) in 1,4-dioxane (15 mL) is added CPhos-G3-palladacycle methanesulfonate and sodium tert-butoxide (216 mg, 16.1 mmol) and degassed withnitrogen for 5 min. The resultant mixture is stirred at 100° C. for 10h. The reaction mixture is filtered through a pad of silica eluting withEtOAc and concentrated. The crude product is purified by silica gelcolumn chromatography to afford the title compound.

Yield: 2.1 g (88%) R_(t)(HPLC): 1.15 min (Method 1)

4-(6-Amino-4-methoxy-pyridin-3-yl)-piperazine-1-carboxylic acidtert-butyl ester

To4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-piperazine-1-carboxylicacid tell-butyl ester (2.1 g, 4.73 mmol) in EtOH (10 mL) and water (5mL) is added hydroxylamine hydrochloride (1.64 g, 23.6 mmol) andtrimethylamine (659 μL, 4.73 mmol) and stirred at 80° C. for 18 h. Thereaction mixture is concentrated under reduced pressure. The residue issuspended in DCM and filtered to remove the salts. The filtrate ispurified by silica gel column chromatography to afford the titlecompound.

Yield: 1.07 g (73%)

4-Methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride

To 4-(6-amino-4-methoxy-pyridin-3-yl)-piperazine-1-carboxylic acidtert-butyl ester (1.07 g, 3.47 mmol) in DCM (12 mL) is added 4M HCl in1,4-dioxane (4.34 mL, 17.35 mmol) and stirred at RT for 2 h. Thereaction mixture is concentrated under reduced pressure.

Yield: 976 mg (quantitative)

6-Amino-4-methyl-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1-carboxylic acidtert-butyl ester

To4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1.24 g, 4.01 mmol) and5-bromo-4-methyl-pyridin-2-ylamine (750 mg, 4.01 mmol) in 1,4-dioxane isadded 2M Na₂CO₃ solution (4.01 mL, 8.02 mmol) and PdCl₂(dppf) (328 mg,0.40 mmol). The reaction mixture is degassed with nitrogen for 5 min.and stirred in the microwave at 150° C. for 30 min. The reaction isdiluted with EtOAc and water and the layers are separated. The aq. layeris extracted again with EtOAc. The combined organic layers are washedwith brine, dried over MgSO₄ and concentrated under vacuum. The residueis purified by silica gel chromatography to give the title compound.

Yield: 1.1 g (95%) ESI-MS: m/z=290 (M+H)⁺ R_(t)(HPLC): 1.82 min (Method2)

6-Amino-4-methyl-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester

To 6-amino-4-methyl-3′,6′-dihydro-2′H-[3,4]bipyridinyl-1′-carboxylicacid tert-butyl ester (1.10 g, 3.80 mmol) in MeOH (10 mL) is added Pd/C(405 mg, 0.38 mmol) under nitrogen. The reaction mixture is degassed andsubjected to a balloon of H₂. The reaction is filtered and concentratedunder reduced pressure. The crude product is purified by silica gelcolumn chromatography to give the title compound.

Yield: 511 mg (46%) ESI-MS: m/z=292 (M+H)⁺ R_(t)(HPLC): 1.80 min (Method2)

4-Methyl-1′,2′,3′,4′,5′,6′-hexahydro[3,4′]bipyridinyl-6-ylaminedihydrochloride

The title compound is synthesized from6-Amino-4-methyl-3′,4′,5′,6′-tetrahydro-2′H-[3,4]bipyridinyl-1′-carboxylicacid tert-butyl ester (511 mg, 1.75 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 347 mg (75%) ESI-MS: m/z=192 (M+H)⁺ R_(t)(HPLC): 0.36 min (Method2)

6-Amino-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester

To4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1.70 g, 5.50 mmol) and 5-bromo-pyridin-2-ylamine(1.00 mg, 5.78 mmol) in 1,4-dioxane is added 2M Na₂CO₃ solution (2 mL,4.00 mmol) and PdCl₂(dppf)CH₂Cl₂ (449 mg, 0.55 mmol). The reactionmixture is degassed with nitrogen for 5 min. and stirred at 120° C. for16 h. All volatiles are evaporated under reduced pressure. The crudematerial is purified by normal phase chromatography to afford the titlecompound.

Yield: 1.2 g (79%)

6-Amino-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester

To 6-amino-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (45.0 g, 163.4 mmol) in EtOH (1000 mL) is added Pd(OH)₂on carbon (4.5 g, 32.4 mmol) under nitrogen. The reaction mixture isstirred at 30PSI in PARR SHAKER for 16 h. The reaction is filteredthrough Celite®. The filtrate is evaporated under reduced pressure andthe residue is purified by silica gel column chromatography to get thetitle compound.

Yield: 23.7 g (79%)

1′,2′,3′,4′,5′,6′-hexahydro[3,4′]bipyridinyl-6-ylamine dihydrochloride

The title compound is synthesized from6-amino-3′,4′,5′,6′-tetrahydro-2′H-[3,4]bipyridinyl-1′-carboxylic acidtert-butyl ester (800 mg, 2.88 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 694 mg (96%)

6-Amino-4-methoxy-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester

To4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (10.0 g, 49.3 mmol) and5-bromo-4-methoxy-pyridin-2-ylamine (15.2 g, 49.3 mmol) in 1,4-dioxane(100 mL) is added 2M Na₂CO₃ solution (2 mL, 148 mmol) andPdCl₂(dppf)CH₂Cl₂ (3.93 g, 4.93 mmol). The reaction mixture is degassedwith nitrogen for 5 min. and stirred at 120° C. for 16 h. All volatilesare evaporated under reduced pressure. The residue is diluted with waterand extracted three times with EtOAc. The combined organic layers arewashed with brine, dried over Na₂SO₄ and concentrated under reducedpressure. The crude material is purified by normal phase chromatographyto afford the title compound.

Yield: 2.50 g (55%)

6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4]bipyridinyl-1′-carboxylicacid tert-butyl ester

The title compound is synthesized from6-amino-4-methoxy-3′,6′-dihydro-2′H-[3,4]bipyridinyl-1′-carboxylic acidtert-butyl ester (750 mg, 2.46 mmol) according to the proceduredescribed for the synthesis of the intermediate6-amino-4-methyl-3′,4′,5′,6′-tetrahydro-2′H-[3,4]bipyridinyl-1′-carboxylicacid tert-butyl ester

Yield: 715 mg (95%) ESI-MS: m/z=308 (M+H)⁺ R_(t)(HPLC): 0.88 min (Method5)

4-Methoxy-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylaminedihydrochloride

The title compound is synthesized from6-amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4]bipyridinyl-1′-carboxylicacid tert-butyl ester (715 mg, 2.33 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 745 mg (quantitative) ESI-MS: m/z=208 (M+H)⁺ R_(t)(HPLC): 0.56min (Method 6)

4-(6-Amino-pyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester

The title compound is synthesized from4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (977 mg, 3.16 mmol) and6-chloro-pyridazin-3-ylamine (500 mg, 2.87 mmol) according to theprocedure described for the synthesis of the intermediate6-amino-4-methoxy-3′,6′-dihydro-2′H-[3,4]bipyridinyl-1′-carboxylic acidtert-butyl ester.

Yield: 590 mg (74.3%) ESI-MS: m/z=276 (M+H)⁺ R_(t)(HPLC): 0.44 min(Method 1)

4-(6-Amino-pyridazin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester

The title compound is synthesized from4-(6-amino-pyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (5.40 g, 19.5 mmol) according to the proceduredescribed for the synthesis of the intermediate6-amino-4-methyl-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester.

Yield: 3.93 g (72%) ESI-MS: m/z=279 (M+H)⁺ R_(t)(HPLC): 0.38 min (Method1)

6-Piperidin-4-yl-pyridazin-3-ylamine dihydrochloride

The title compound is synthesized from4-(6-amino-pyridazin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester(3.60 g, 12.9 mmol) according to the procedure described for thesynthesis of the intermediate4-methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 2.30 g (quantitative) ESI-MS: m/z=179 (M+H)⁺ R_(t)(HPLC): 0.32min (Method 1)

(R)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-piperazine-1-carboxylicacid tert-butyl ester

To (R)-2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester(1.00 g, 4.62 mmol) in DMA (10 mL) is addedtert-butyl-chloro-dimethyl-silane (1.05 g, 6.94 mmol) and imidazole (944mg, 13.9 mmol). and the reaction mixture is stirred for 14 h at rt. Thereaction mixture is diluted with EtOAc and washed with water and brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue is purified by silica gel column chromatography to give thetitle compound.

Yield: 1.45 g (95%)

5-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-pyridine

To 5-bromo-4-methyl-pyridin-2-ylamine (2.00 g, 10.7 mmol) andhexane-2,5-dione (1.47 g, 12.8 mmol) in toluene (50 mL) is added paratoluene sulfonic acid (61.0 mg, 0.32 mmol), and the reaction mixture isstirred for 18 h at 140° C. The reaction mixture is poured into waterand diluted in EtOAc. The separated organic layer is washed with brineand dried over MgSO₄, filtered and concentrated under reduced pressure.The residue is purified by silica gel column chromatography to give thetitle compound.

Yield: 2.68 g (95%)

(R)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-pyridin-3-yl]-piperazine-1-carboxylicacid tert-butyl ester

To 5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-pyridine (1.00 g, 3.77mmol) and(R)-2-(tert-butyl-dimethyl-silanyloxymethyl)-piperazine-1-carboxylicacid tert-butyl ester (1.25 g, 3.77 mmol) in 1,4-dioxane (13 mL) isadded sodium tert-butoxide (1.09 g, 11.3 mmol) and CPhos-G3-palladacyclemethane sulfonate (152 mg, 0.19 mmol. The mixture is degassed withnitrogen for 5 min, and stirred for 18 h at 100° C. The reaction mixtureis filtered through a pad of silica gel and eluted with EtOAc. Thefiltrate is concentrated under reduced pressure to afford the titlecompound.

Yield: 1.67 g (86%) ESI-MS: m/z=515 (M+H)⁺ R_(t)(HPLC): 1.56 min (Method1)

(R)-4-(6-Amino-4-methyl-pyridin-3-yl)-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester

A mixture of(R)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-pyridin-3-yl]-piperazine-1-carboxylicacid tert-butyl ester (1.67 g, 3.24 mmol), hydroxylamine hydrochloride(1.13 g, 16.2 mmol) and trimethylamine (452 μL, 3.24 mmol) in ethanol(10 mL) and water (5 mL) is stirred for 18 h at 80° C. The reactionmixture is concentrated under reduced pressure and the residue ispurified by reverse phase chromatography to afford the title compound.

Yield: 1.67 g (86%) R_(t)(HPLC): 0.66 min (Method 3)

[(R)-4-(6-Amino-4-methyl-pyridin-3-yl)-piperazin-2-yl]-methanoldihydrochloride

The title compound is synthesized from(R)-4-(6-amino-4-methyl-pyridin-3-yl)-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester (450 mg, 1.40 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 412 mg (quantitative)

5-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridine

The title compound is synthesized from5-bromo-4-methoxy-pyridin-2-ylamine (2.00 g, 9.85 mmol) according to theprocedure described for the synthesis of the intermediate5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-pyridine.

Yield: 2.48 g, (90%) ESI-MS: m/z=283 (M+H)⁺ R_(t)(HPLC): 2.13 min(Method 5)

7-[6-(2,5-Dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-4,7-diaza-spiro[2.5]octane-4-carboxylicacid tert-butyl ester

To 5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridine (1.25 g, 4.45mmol) and 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester(1.13 g, 5.34 mmol) in 1,4-dioxane (13 mL) is added Cs₂CO₃ (4.35 g, 13.3mmol) and CPhos-G3-palladacycle methane sulfonate (359 mg, 0.45 mmol.The mixture is degassed with nitrogen for 5 min, and stirred for 18 h at100° C. The reaction mixture is extracted with EtOAc, washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue is purified by silica gel column chromatography to afford thetitle compound.

Yield: 1.51 g (82%) ESI-MS: m/z=413 (M+H)⁺ R_(t)(HPLC): 2.69 min (Method5)

7-(6-Amino-4-methoxy-pyridin-3-yl)-4,7-diaza-spiro[2.5]octane-4-carboxylicacid tert-butyl ester

The title compound is synthesized from7-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-4,7-diaza-spiro[2.5]octane-4-carboxylicacid tert-butyl ester (1.51 g, 3.66 mmol) according to the proceduredescribed for the synthesis of the intermediate(R)-4-(6-amino-4-methyl-pyridin-3-yl)-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester

Yield: 1.07 g (87%) ESI-MS: m/z=335 (M+H)⁺ R_(t)(HPLC): 0.74 min (Method5)

5-(4,7-Diaza-spiro[2.5]oct-7-yl)-4-methoxy-pyridin-2-ylaminedihydrochloride

The title compound is synthesized from7-(6-amino-4-methoxy-pyridin-3-yl)-4,7-diaza-spiro[2.5]octane-4-carboxylicacid tert-butyl ester (1.07 g, 3.19 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 1.10 g (quantitative) ESI-MS: m/z=235 (M+H)⁺ R_(t)(HPLC): 0.17min (Method 5)

4-(6-Amino-5-methoxy-pyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

The title compound is synthesized from4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1.74 g, 5.64 mmol) and6-chloro-4-methoxy-pyridazin-3-ylamine (900 mg, 5.64 mmol) according tothe procedure described for the synthesis of the intermediate6-amino-4-methoxy-3′,6′-dihydro-2′H-[3,4]bipyridinyl-1′-carboxylic acidtert-butyl ester

Yield: 787 mg (46%) ESI-MS: m/z=307 (M+H)⁺ R_(t)(HPLC): 0.59 min (Method5)

4-(6-Amino-5-methoxy-pyridazin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester

To4-(6-amino-5-methoxy-pyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (785 mg, 2.56 mmol) in MeOH (10 mL) and aceticacid (1 mL) is added Pd/C (273 mg, 0.26 mmol) under nitrogen. Thereaction mixture is degassed and subjected to a balloon of H₂. Thereaction is filtered and concentrated under reduced pressure. The crudeproduct is purified by silica gel column chromatography to give thetitle compound.

Yield: 513 mg (65%) ESI-MS: m/z=309 (M+H)⁺ R_(t)(HPLC): 0.54 min (Method5)

4-Methoxy-6-piperidin-4-yl-pyridazin-3-ylamine dihydrochloride

The title compound is synthesized from4-(6-amino-5-methoxy-pyridazin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester (510 mg, 1.65 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 514 mg (quantitative) ESI-MS: m/z=209 (M+H)⁺ R_(t)(HPLC): 0.14min (Method 5)

tert-Butyl4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate

The title compound is synthesized from tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(4.76 g, 20 mmol) and tert-butylN-(6-chloro-5-methoxypyridazin-3-yl)carbamate (4.00 g, 20 mmol)according to the procedure described for the synthesis of theintermediate6-amino-4-methoxy-3′,6′-dihydro-2′H-[3,4]bipyridinyl-1′-carboxylic acidtert-butyl ester.

Yield: 4.56 g (59%)

tert-Butyl4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)piperidine-1-carboxylate

To tert-butyl4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(1.50 g, 3.69 mmol) in MeOH (15 mL) is added Pd/C (1.18 g, 1.11 mmol)under a nitrogen atmosphere. The reaction mixture is degassed andsubjected at 30° C. overnight to a balloon of H₂. The mixture is treatedwith Pd/C (0.3 g) and stirred at 30° C. for 3 h. The reaction isfiltered and concentrated under reduced pressure.

Yield: 1.42 g (94%)

5-Methoxy-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride

The title compound is synthesized from tert-butyl4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)piperidine-1-carboxylate(1.42 g, 3.48 mmol) according to the procedure described for thesynthesis of 4-methoxy-5-piperazin-1-yl-pyridin-2-ylaminedihydrochloride.

Yield: 0.99 g (quantitative)

4-(6-Nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester

5-Bromo-2-nitro-pyridine (5.00 g, 24.63 mmol) andpiperazine-1-carboxylic acid tert-butyl ester (13.7 g, 73.9 mmol) in NMP(50 mL) is stirred for 3 h at 120° C. The reaction mixture is pouredinto water. The precipitate is filtered, washed with water and dried togive the title compound.

Yield: 6.80 g (90%)

4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester

4-(6-Nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester(2.00 g, 65.9 mmol) and Pd/C (200 mg) in ethanol is stirred with an H₂balloon for 3 h. The reaction mixture is filtered and the filtrate isconcentrated under reduced pressure.

Yield: 1.90 g (quantitative)

5-Piperazin-1-yl-pyridin-2-ylamine dihydrochloride

4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester(2.50 g, 8.98 mmol) in DCM (30 mL) and 4M HCl in 1,4-dioxane (11.2 mL,44.9 mmol) is stirred for 16 h at rt. The reaction mixture is filteredand washed with ether to give the title compound.

Yield: 2.23 g (99%)

(R)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylicacid tert-butyl ester

To (R)-2-(tert-butyl-dimethyl-silanyloxymethyl)-piperazine-1-carboxylicacid tert-butyl ester (1.50 g, 4.54 mmol) and 5-bromo-2-nitropyridine(1.00 g, 4.93 mmol) in 1,4-dioxane (12 mL) is added Cs₂CO₃ (4.44 g, 13.6mmol), Pd₂(dba)₃ (208 mg, 0.23 mmol) and Xantphos (263 mg, 0.45 mmol).The reaction mixture is stirred at 100° C. for 24 h, filtered throughCelite®, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography to afford the titlecompound.

Yield: 1.35 g (66%) ESI-MS: m/z=453 (M+H)⁺ R_(t)(HPLC): 1.31 min (Method1)

(R)-4-(6-Amino-pyridin-3-yl)-2-(tert-butyl-dimethyl-silanyloxymethyl)-piperazine-1-carboxylicacid tert-butyl ester

(R)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylicacid tert-butyl ester (1.35 g, 2.98 mmol) and Pd/C (317 mg, 0.15 mmol)in methanol (20 mL) is stirred with an H₂ balloon for 24 h. The reactionmixture is filtered through Celite®, washed with methanol, and thefiltrate is concentrated under reduced pressure.

Yield: 1.26 g (quantitative)

[(R)-4-(6-Amino-pyridin-3-yl)-piperazin-2-yl]-methanol dihydrochloride

(R)-4-(6-Amino-pyridin-3-yl)-2-(tert-butyl-dimethyl-silanyloxymethyl)-piperazine-1-carboxylicacid tert-butyl ester (1.26 g, 2.98 mmol) in DCM (10 mL) and 4M HCl in1,4-dioxane (7.5 mL, 30.0 mmol) is stirred for 1 h at rt. The reactionmixture is concentrated under reduced pressure, slurried in ether,filtered and washed with ether to give the title compound.

Yield: 838 mg (quantitative)

(R)-4-[6-(2,5-Dimethyl-pyrrol-1-yl)-4-methyl-pyridin-3-yl]-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester

To(R)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-pyridin-3-yl]piperazine-1-carboxylicacid tert-butyl ester (8.56 g, 16.1 mmol) in THF (100 mL) is addedtetrabutylammonium fluoride (16.1 mL, 16.1 mmol), and the reactionmixture is stirred at RT for 1.5 h. The reaction mixture is concentratedunder reduced pressure and the residue is purified by silica gel columnchromatography to afford the title compound.

Yield: 6.10 g (91%) ESI-MS: m/z=417 (M+H)⁺ R_(t)(HPLC): 0.98 min (Method1)

(R)-4-[6-(2,5-Dimethyl4-pyrrol-1-yl)-4-methyl-pyridin-3-yl]-2-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester

To(R)-4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-pyridin-3-yl]-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester (2.00 g, 4.80 mmol) and methyl iodide (915 mg,7.20 mmol) in DMA (15 mL) is added 60% NaH (230 mg, 5.76 mmol). Thereaction mixture is stirred for 2 h at RT and quenched with water. Themixture is extracted three times with EtOAc, the combined organic layersare washed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure. The residue is purified by silica gel columnchromatography to give the title compound.

Yield: 1.80 g (87%) ESI-MS: m/z=431 (M+H)⁺ R_(t)(HPLC): 1.12 min (Method1)

(R)-4-(6-Amino-4-methyl-pyridin-3-yl)-2-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester

The title compound is synthesized from(R)-4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methylpyridin-3-yl]-2-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester (1.80 g, 4.18 mmol) according to the proceduredescribed for the synthesis of the intermediate(R)-4-(6-amino-4-methyl-pyridin-3-yl)-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester

Yield: 1.07 g (87%) ESI-MS: m/z=353 (M+H)⁺ R_(t)(HPLC): 0.44 min (Method1)

5-((R)-3-Methoxymethyl-piperazin-1-yl)-4-methyl-pyridin-2-ylaminedihydrochloride

The title compound is synthesized from(R)-4-(6-amino-4-methyl-pyridin-3-yl)-2-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester (440 mg, 1.25 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 406 mg (quantitative)

4-(6-Amino-4-methyl-pyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

The title compound is synthesized from4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (538 mg, 1.74 mmol) and6-chloro-5-methyl-pyridazin-3-ylamine (250 mg, 1.74 mmol) according tothe procedure described for the synthesis of the intermediate6-Amino-4-methyl-3′,6′-dihydro-2′H-[3,4]bipyridinyl-1′-carboxylic acidtert-butyl ester.

Yield: 326 mg (65%) ESI-MS: m/z=292 (M+H)⁺ R_(t)(HPLC): 0.51 min (Method5)

4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester

The title compound is synthesized from4-(6-amino-4-methyl-pyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (326 mg, 1.12 mmol) according to the proceduredescribed for the synthesis of the intermediate6-amino-4-methyl-3′,4′,5′,6′-tetrahydro-2′H-[3,4]bipyridinyl-1′-carboxylicacid tert-butyl ester.

Yield: 289 mg (88%) ESI-MS: m/z=293 (M+H)⁺ R_(t)(HPLC): 0.60 min (Method5)

5-Methyl-6-piperidin-4-yl-pyridazin-3-ylamine dihydrochloride

The title compound is synthesized from4-(6-amino-4-methyl-pyridazin-3-yl)-piperidine-1-carboxylic acidtert-butyl ester (175 mg, 0.60 mmol) according to the proceduredescribed for the synthesis of the intermediate5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 154 mg (97%) ESI-MS: m/z=193 (M+H)⁺ R_(t)(HPLC): 0.46 min (Method2)

5-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridine

The title compound is synthesized from5-bromo-4-methoxy-pyridin-2-ylamine (10.6 g, 52.1 mmol) according to theprocedure described for the synthesis of the intermediate5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-pyridine.

Yield: 14.0 g (96%) ESI-MS: m/z=283 (M+H)⁺ R_(t)(HPLC): 0.93 min (Method3)

(R)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-piperazine-1-carboxylicacid tert-butyl ester

To 5-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridine (1.24 g, 4.41mmol) and(R)-2-(tert-butyl-dimethyl-silanyloxymethyl)-piperazine-1-carboxylicacid tert-butyl ester (1.46 g, 4.41 mmol) in 1,4-dioxane (13 mL) isadded sodium tert-butoxide (1.27 g, 13.2 mmol) and CPhos-G3-palladacyclemethane sulfonate (178 mg, 0.22 mmol). The mixture is degassed withnitrogen for 5 min, and stirred for 4 h at 100° C. The reaction mixtureis filtered through a pad of silica gel and eluted with EtOAc. Thefiltrate is concentrated under reduced pressure and the residue ispurified by reverse phase column chromatography to give the titlecompound.

Yield: 1.68 g (72%) ESI-MS: m/z=531 (M+H)⁺ R_(t)(HPLC): 1.43 min

(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester

(R)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-piperazine-1-carboxylicacid tert-butyl ester (1.68 g, 3.17 mmol), hydroxylamine hydrochloride(1.10 g, 15.8 mmol) and trimethylamine (320 μl, 3.24 mmol) in ethanol (6mL) and water (3 mL) is stirred for 18 h at 80° C. Hydroxylaminehydrochloride (440 mg, 6.33 mmol) is added again and stirred at 80° C.The reaction mixture is concentrated under reduced pressure and theresidue is purified by reverse phase column chromatography (to affordthe title compound.

Yield: 620 mg (58%)

[(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-piperazin-2-yl]-methanolhydrochloride

The title compound is synthesized from(R)-4-(6-amino-4-methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester (620 mg, 1.83 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 503 mg (quantitative)

3-[6-(2,5-Dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

To 5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridine (1.00 g, 3.56mmol) and 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butylester (830 mg, 3.91 mmol) in 1,4-dioxane (13 mL) is added sodiumtert-butoxide (3.48 g, 10.7 mmol) and CPhos-G3-palladacycle methanesulfonate (287 mg, 0.36 mmol). The mixture is degassed with nitrogen for5 min, and stirred for 18 h at 80° C. The reaction mixture is extractedwith EtOAc, washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography to give the title compound.

Yield: 760 mg (52%) ESI-MS: m/z=412 (M+H)⁺ R_(t)(HPLC): 1.23 min (Method1)

3-(6-Amino-4-methoxy-pyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

The title compound is synthesized from3-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (760 mg, 1.84 mmol) according to the proceduredescribed for the synthesis of the intermediate4-(6-amino-4-methoxy-pyridin-3-yl)-piperazine-1-carboxylic acidtert-butyl ester.

Yield: 330 mg (54%) ESI-MS: m/z=335 (M+H)⁺ R_(t)(HPLC): 1.75 min (Method6)

5-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-4-methoxy-pyridin-2-ylaminedihydrochloride

The title compound is synthesized from3-(6-amino-4-methoxy-pyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (330 mg, 0.99 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 330 mg (quantitative) ESI-MS: m/z=235 (M+H)⁺ R_(t)(HPLC): 0.15min (Method 5)

4-Benzyl 1-tert-butyl(2R)-2-[methoxy(methyl)carbamoyl]piperazine-1,4-dicarboxylate

(2R)-4-[(benzyloxy)carbonyl]-1-[(tert-butoxy)carbonyl]piperazine-2-carboxylicacid (4.00 g, 11.0 mmol), DIPEA (5.1 mL, 27.4 mmol), HATU (5.01 g, 13.2mmol) and N,O-dimethylhydroxylamine hydrochloride (1.29 g, 13.2 mmol) inDMA (40 mL) are stirred at RT for 3 days. The reaction mixture isdiluted with EtOAc, washed with water and brine. The organic layer isdried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue is purified by silica gel column chromatography to give thetitle compound.

Yield: 4.44 g (99%) ESI-MS: m/z=408 (M+H)⁺

4-Benzyl 1-tert-butyl (2R)-2-acetylpiperazine-1,4-dicarboxylate

To a −20° C. cooled mixture of 4-benzyl 1-tert-butyl(2R)-2-[methoxy(methyl)carbamoyl]-piperazine-1,4-dicarboxylate (4.40 g,10.80 mmol) in THF (25 mL) is added dropwise methyl magnesium bromide(5.40 mL, 16.20 mmol) and stirred at −20° C. for 30 min. The reactionmixture is quenched with saturated, aqueous NH₄Cl solution, diluted withEtOAc, and washed with water +1N HCl and brine. The organic layer isdried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue is purified by chromatography to give the desired product.Further purification is done by chiral chromatography separation to givethe pure R enantiomer.

Yield: 2.38 g (61%)

4-Benzyl 1-tert-butyl(2R)-2-(1-hydroxyethyyl)piperazine-1,4-dicarboxylate

Sodium borohydride (0.36 g, 9.52 mmol) is added to (4-benzyl1-tert-butyl (2R)-2-acetylpiperazine-1,4-dicarboxylate (2.30 g, 6.35mmol) in methanol (100 mL). After stirring the reaction mixture for 30min, the solvent is removed under reduced pressure. The residue ispurified by silica chromatography.

Yield: 2.10 g (91%)

4-Benzyl 1-tert-butyl(2R)-2-{1-[(tert-butyldimethylsilyl)oxy]ethyl}piperazine-1,4-dicarboxylate

tert-Butyl(chloro)dimethylsilane (1.30 g, 8.64 mmol) is added to4-benzyl 1-tert-butyl(2R)-2-(1-hydroxyethyl)piperazine-1,4-dicarboxylate (2.10 g, 5.76 mmol)and imidazole (1.18 g, 17.29 mmol) in dichloromethane (15 mL). Thereaction mixture is stirred overnight. After adding water (10 mL), theaqueous layer is extracted with dichloromethane (2×25 mL). The combinedorganic layers are washed with brine. The organic layer is dried,filtered and concentrated under reduced pressure. The residue ispurified by silica chromatography.

Yield: 2.75 g (99.7%)

tert-Butyl(2R)-2-{1-[(tert-butyldimethylsilyl)oxy]ethyl}piperazine-1-carboxylate

Under an hydrogen atmosphere (balloon) 4-benzyl 1-tert-butyl(2R)-2-{1-[(tert-butyldimethylsilyl)-oxy]ethyl}piperazine-1,4-dicarboxylate(2.75 g, 5.75 mmol) and Pd/C (0.20 g) is stirred at room temperature inethanol (50 mL) for 2 h. After removal of the catalyst by filteringthrough Celite®, the solvent is removed under reduced pressure. Theresidue is filtered through silica eluting with 10% MeOH/dichlormethane.

Yield: 1.89 g (96%)

(tert-Butyl(2R)-2-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridin-3-yl]piperazine-1-carbonylate

To tert-Butyl(2R)-2-{1-[(tert-butyldimethylsilyl)oxy]ethyl}piperazine-1-carboxylate(1.89 g, 5.49 mmol) and5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridine (1.54 g, 5.49mmol) in 1,4-dioxane (20 mL) is added CPhos-G3-palladacycle methanesulfonate (0.22 g) and sodium tert-butoxide (1.58 g, 16.5 mmol), and thereaction mixture is sparged with nitrogen. The reaction mixture isstirred at 100° C. for 10 h. The reaction mixture is filtered through apad of silica eluting with EtOAc and concentrated. The residue ispurified twice by silica chromatography to afford the title compounds.

Yield:

tert-butyl(2R)-2-[(1S)-1-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridin-3-yl]piperazine-1-carboxylate:0.57 g (19%) and tert-butyl(2R)-2-[(1R)-1-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridin-3-yl]piperazine-1-carboxylate:0.78 g (26%)

tert-Butyl(2R)-4-(6-amino-4-methoxypyridin-3-yl)-2-[(1R)-1-hydroxyethyl]piperazine-1-carboxylate

tert-Butyl(2R)-2-[(1R)-1-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridin-3-yl]piperazine-1-carboxylate(0.87 g, 1.60 mmol), hydroxylamine hydrochloride (0.56 g, 7.99 mmol) andtrimethylamine (0.22 mL, 1.60 mmol) in 8 mL ethanol and 4 mL water isheated at 80° C. for 42 h. An additional amount of hydroxylaminehydrochloride (0.22 g, 3.19 mmol) is added and the reaction mixture isstirred at 80° C. overnight. The reaction mixture is concentrated underreduced pressure, taken up in dichloromethane and filtered. The desiredcompound is purified by silica chromatography

Yield: 0.20 g (36%),

(1R)-1-[(2R)-4-(6-Amino-4-methoxypyridin-3-yl)piperazin-2-yl]ethan-1-oldihydrochloride

4N HCl in dioxane (0.71 mL, 2.84 mmol) is added to tert-butyl(2R)-4-(6-amino-4-methoxypyridin-3-yl)-2-[(1R)-1-hydroxyethyl]piperazine-1-carboxylate(0.20 g, 0.57 mmol) in 5 mL dichloromethane and stirred at RT for 2 h.Additional 1 mL of 4N HCl in dioxane is added and stirred 1 h at RT. Thereaction mixture is concentrated under reduced pressure. The residue isused without further purification.

Yield: 0.18 g (quantitative)

tert-Butyl(2R)-4-(6-amino-4-methoxypyridin-3-yl)-2-[(1S)-1-hydroxyethyl]piperazine-1-carboxylate

tert-Butyl(2R)-2-[(1S)-1-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridin-3-yl]piperazine-1-carboxylate(0.57 g, 1.04 mmol), hydroxylamine hydrochloride (0.36 g, 5.21 mmol) andtrimethylamine (0.15 mL, 1.04 mmol) in 4 mL ethanol and 2 mL water isheated at 80° C. for 42 h. Additional amount of hydroxylaminehydrochloride (0.15 g, 2.09 mmol) is added and the reaction mixture isstirred at 80° C. overnight. The reaction mixture is concentrated underreduced pressure, taken up in dichloromethane and filtered. The desiredcompound is purified by silica chromatography and repurified by HPLC

Yield: 0.12 g (33%),

(1S)-1-[(2R)-4-(6-Amino-4-methoxypyridin-3-yl)piperazin-2-yl]ethan-1-oldihydrochloride

4N HCl in dioxane (0.50 mL, 2.00 mmol) is added to tert-butyl(2R)-4-(6-amino-4-methoxypyridin-3-yl)-2-[(1S)-1-hydroxyethyl]piperazine-1-carboxylate(0.12 g, 0.34 mmol) in 1 mL dichloromethane and stirred at RT for 1 h.The reaction mixture is concentrated under reduced pressure. The residueis used without further purification.

Yield: quantitative

7-(6-Amino-4-methoxy-pyridin-3-yl)-3-oxa-9-aza-bicyclo[3.3.1]non-6-ene-9-carboxylicacid tert-butyl ester

The title compound is synthesized from5-bromo-4-methoxy-pyridin-2-ylamine (202 mg, 1.00 mmol) and7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-oxa-9-aza-bicyclo[3.3.1]non-6-ene-9-carboxylicacid tert-butyl ester (350 mg, 1.00 mmol) according to the proceduredescribed for the synthesis of the intermediate6-amino-4-methyl-3′,6′-dihydro-2′H-[3,4]bipyridinyl-1′-carboxylic acidtert-butyl ester.

Yield: 220 mg (64%) ESI-MS: m/z=348 (M+H)⁺ R_(t)(HPLC): 1.52 min (Method2)

7-(6-Amino-4-methoxy-pyridin-3-yl)-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylicacid tert-butyl ester

To7-(6-amino-4-methoxy-pyridin-3-yl)-3-oxa-9-aza-bicyclo[3.3.1]non-6-ene-9-carboxylicacid tert-butyl ester (220 mg, 0.63 mmol) in EtOAc (10 mL) is added Pd/C(67.0 mg, 0.06 mmol) under nitrogen. The reaction mixture is degassed,placed under a balloon of H₂ and stirred for 18 h at 50° C. The reactionis filtered through Celite®, concentrated under reduced pressure andpurified by silica gel column chromatography to give the title compound.

Yield: 145 mg (66%) ESI-MS: m/z=350 (M+H)⁺ R_(t)(HPLC): 1.60 min (Method2)

4-Methoxy-5-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-pyridin-2-ylaminedihydrochloride

The title compound is synthesized from7-(6-amino-4-methoxy-pyridin-3-yl)-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylicacid tert-butyl ester (145 mg, 0.41 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 133 mg (quantitative) ESI-MS: m/z=250 (M+H)⁺ R_(t)(HPLC): 0.15min (Method 5)

(S)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-piperazine-1-carboxylicacid tert-butyl ester

To (S)-2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester(2.00 g, 9.25 mmol) in DMA (10 mL) is addedtert-butyl-chloro-dimethyl-silane (2.09 g, 13.9 mmol) and imidazole(1.89 g, 27.7 mmol), and the reaction mixture is stirred for 24 h at rt.The reaction mixture is diluted with NH₄Cl-solution and extracted withEtOAc. The organic layer is washed with water and brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography to give the title compound.

Yield: 2.80 g (92%)

(S)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-piperazine-1-carboxylicacid tert-butylester

The title compound is synthesized from5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridine (3.25 g, 11.6mmol) and(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-piperazine-1-carboxylicacid tert-butyl (3.82 g, 11.6 mmol) ester according to the proceduredescribed for the synthesis of the intermediate3-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester.

Yield: 4.94 g (73%) ESI-MS: m/z=531 (M+H)⁺ R_(t)(HPLC): 1.49 min (Method3)

(S)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester

(S)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methoxypyridin-3-yl]-piperazine-1-carboxylicacid tert-butyl ester (11.9 g, 22.4 mmol), hydroxylamine hydrochloride(3.89 g, 56.0 mmol) and trimethylamine (7.8 mL, 56.0 mmol) in ethanol(30 mL) and water (15 mL) are stirred for 18 h at 80° C. The reactionmixture is concentrated under reduced pressure and the residue ispurified by silica gel chromatography to give the title compound.

Yield: 2.57 g (68%)

(S)-4-(6-Amino-4-methoxy-pyridin-3-yl)-piperazin-2-yl]-methanolhydrochloride

The title compound is synthesized from(S)-4-(6-amino-4-methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester (264 mg, 0.58 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 160 mg (quantitative)

(R)-4-[6-(2,5-Dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester

To(R)-2-(tert-butyl-dimethyl-silanyloxymethyl)-4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-piperazine-1-carboxylicacid tert-butyl ester (8.56 g, 16.1 mmol) in THF (100 mL) is added TBAF(1M in THF, 16.1 mL, 16.1 mmol). The reaction mixture is stirred for 2.5h at rt. The reaction mixture is concentrated under reduced pressure andthe residue is purified by chromatography to get the title product.

Yield: 180 mg (87%)

(R)-4-[6-(2,5-Dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-2-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester

NaH (60%, 230 mg, 9.58 mmol) is added to(R)-4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester (2.0 g, 4.80 mmol) and Mel (401 μL, 7.20 mmol) inDMA (20 mL). The reaction mixture is stirred for 2 h at rt. Water isadded and the reaction mixture is extracted with EtOAc (3 times). Thecombined organic layers are washed with brine, dried over MgSO₄,filtered and concentrated under reduced pressure. The residue ispurified by normal phase chromatography.

Yield: 1.8 g (87%) ESI-MS: m/z=431 (M+H)⁺ R_(t)(HPLC): 1.11 min (Method1)

(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester

(R)-4-[6-(2,5-Dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-2-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester (1.8 g, 4.18 mmol), hydroxylamine hydrochloride(1.45 g, 20.9 mmol) and trimethylamine (0.58 mL, 4.18 mmol) in ethanol(10 mL) and water (5 mL) are stirred at 80° C. for 18 h. The reactionmixture is concentrated under reduced pressure, slurried in DCM,filtered to remove salts and concentrated again under reduced pressure.The residue is purified by normal phase column chromatography to givethe title product.

Yield: 440 mg (30%) ESI-MS: m/z=353 (M+H)⁺ R_(t)(HPLC): 0.44 min (Method1)

4-Methoxy-5-((R)-3-methoxymethyl-piperazin-1-yl)-pyridin-2-ylaminedihydrochloride

The title compound is synthesized from(R)-4-(6-amino-4-methoxy-pyridin-3-yl)-2-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester (440 mg, 1.25 mmol) according to the proceduredescribed for the synthesis of the intermediate[(R)-4-(6-amino-4-methoxy-pyridin-3-yl)-piperazin-2-yl]methanolhydrochloride.

Yield: 406 mg (quantitative)

5-Fluoro-4-methoxy-pyridine-2-carbonitrile

2-Chloro-5-fluoro-4-methoxy-pyridine (1.00 g, 6.19 mmol) is taken in asealed tube. Zinc cyanide (799 mg, 6.81 mmol) and zinc (40.5 mg, 0.31mmol) are added and purged with argon. Then PdCl₂(dppf)CH₂Cl₂ (253 mg,0.62 mmol) and NMP are added and the mixture is heated for 45 min. at150° C. in the microwave. Water and EtOAc are added to the reactionmixture and filtered through Celite®. The organic layer is washed withsodium bicarbonate solution, water, brine and dried over MgSO₄, filteredand concentrated under reduced pressure. The residue is purified bysilica gel column chromatography to afford the title compound.

Yield: 689 mg (73%) ESI-MS: m/z=153 (M+H)⁺ R_(t)(HPLC): 0.61 min (Method1)

5-(4-Fluoro-phenoxy)-4-methoxy-pyridine-2-carbonitrile

5-Fluoro-4-methoxy-pyridine-2-carbonitrile (6.00 g, 39.4 mmol),4-fluorophenol (5.31 g, 47.3 mmol) and K₂CO₃ (12.0 g, 86.8 mmol) in NMP(12 mL) are heated at 100° C. for 3 h in a sealed tube. The reactionmixture is diluted with water and extracted with EtOAc. The organiclayer is washed with brine and dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue is triturated by etherand heptane to give the title compound.

Yield: 8.99 g (93%) ESI-MS: m/z=245 (M+H)⁺ R_(t)(HPLC): 0.91 min (Method1)

5-(4-Fluoro-phenoxy)-4-methoxy-pyridine-2-carboxylic acid

5-(4-Fluoro-phenoxy)-4-methoxy-pyridine-2-carbonitrile (8.50 g, 34.8mmol) in aqueous 2N NaOH solution (90 mL) is stirred at 100° C. for 6 h.The reaction mixture is cooled to RT and the pH of the solution isadjusted to pH 4.5 with 4 N HCl. The precipitate is collected and driedin a drying oven to give the title compound.

Yield: 8.80 g (96%) ESI-MS: m/z=264 (M+H)⁺ R_(t)(HPLC): 1.58 min (Method4)

4-Methoxy-5-phenoxy-pyridine-2-carbonitrile

5-Fluoro-4-methoxy-pyridine-2-carbonitrile (8.00 g, 52.6 mmol), phenol(5.94 g, 63.1 mmol) and K₂CO₃ (16.0 g, 115 mmol) in NMP (3 mL) areheated at 100° C. for 3 h in a sealed tube. The reaction mixture isdiluted with water and extracted with EtOAc. The organic layer is washedwith brine and dried over MgSO₄, filtered and concentrated under reducedpressure. The residue is purified by silica gel chromatography to givethe title compound.

Yield: 11.5 g (93%) ESI-MS: m/z=227 (M+H)⁺ R_(t)(HPLC): 0.92 min (Method1)

4-Methoxy-5-phenoxy-pyridine-2-carboxylic acid

The title compound is synthesized from4-methoxy-5-phenoxy-pyridine-2-carbonitrile (11.5 g, 50.8 mmol)according to the procedure described for the synthesis of theintermediate 5-(4-fluoro-phenoxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 9.57 g (77%) ESI-MS: m/z=246 (M+H)⁺ R_(t)(HPLC): 2.64 min (Method4)

5-(4-Isopropoxy-phenoxy)-4-methoxy-pyridine-2-carbonitrile

The title compound is synthesized from5-fluoro-4-methoxy-pyridine-2-carbonitrile (500 mg, 3.29 mmol) and4-isopropoxy-phenol (600 mg, 3.94 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-phenoxy-pyridine-2-carbonitrile.

Yield: 850 mg (91%) ESI-MS: m/z=285 (M+H)⁺ R_(t)(HPLC): 1.02 min (Method1)

5-(4-Isopropoxy-phenoxy)-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-(4-isopropoxy-phenoxy)-4-methoxy-pyridine-2-carbonitrile (200 mg, 0.70mmol) according to the procedure described for the synthesis of theintermediate 5-(4-fluoro-phenoxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 190 mg (77%) R_(t)(HPLC): 0.73 min (Method 1)

4-Methoxy-5-(4-methoxy-phenoxy)-pyridine-2-carbonitrile

The title compound is synthesized from5-fluoro-4-methoxy-pyridine-2-carbonitrile (500 mg, 3.29 mmol) and4-methoxyphenol (490 mg, 3.94 mmol) according to the procedure describedfor the synthesis of the intermediate4-methoxy-5-phenoxy-pyridine-2-carbonitrile.

Yield: 740 mg (88%)

4-Methoxy-5-(4-methoxy-phenoxy)-pyridine-2-carboxylic acid

The title compound is synthesized from4-methoxy-5-(4-methoxy-phenoxy)-pyridine-2-carbonitrile (740 mg, 2.89mmol) according to the procedure described for the synthesis of theintermediate 5-(4-fluoro-phenoxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 610 mg (77%)

4-Methoxy-5-(4-trifluoromethyl-phenoxy)-pyridine-2-carbonitrile

The title compound is synthesized from5-fluoro-4-methoxy-pyridine-2-carbonitrile (500 mg, 3.29 mmol) and4-trifluoromethyl-phenol (639 mg, 3.94 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-phenoxy-pyridine-2-carbonitrile.

Yield: 320 mg (33%) ESI-MS: m/z=294 (M+H)⁺ R_(t)(HPLC): 1.06 min (Method1)

4-Methoxy-5-(4-trifluoromethyl-phenoxy)-pyridine-2-carboxylic acid

The title compound is synthesized from4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridine-2-carbonitrile (151 mg,0.51 mmol) according to the procedure described for the synthesis of theintermediate 5-(4-fluoro-phenoxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 150 mg (93%)

5-(4-Chloro-phenoxy)-4-methoxy-pyridine-2-carbonitrile

The title compound is synthesized from5-fluoro-4-methoxy-pyridine-2-carbonitrile (500 mg, 3.29 mmol) and4-chlorophenol (507 mg, 3.94 mmol) according to the procedure describedfor the synthesis of the intermediate4-methoxy-5-phenoxy-pyridine-2-carbonitrile.

Yield: 695 mg (81%)

5-(4-Chloro-phenoxy)-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-(4-chloro-phenoxy)-4-methoxy-pyridine-2-carbonitrile (645 mg, 2.47mmol) according to the procedure described for the synthesis of theintermediate 5-(4-fluoro-phenoxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 622 mg (90%) ESI-MS: m/z=280 (M+H)⁺

5-(4-Difluoromethoxy-phenoxy)-4-methoxy-pyridine-2-carbonitrile

The title compound is synthesized from5-fluoro-4-methoxy-pyridine-2-carbonitrile (75.0 mg, 0.49 mmol) and4-difluoromethoxy-phenol (101 mg, 0.63 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-phenoxy-pyridine-2-carbonitrile.

Yield: 98.0 mg (68%) R_(t)(HPLC): 0.93 min (Method 1)

5-(4-Difluoromethoxy-phenoxy)-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-(4-difluoromethoxy-phenoxy)-4-methoxy-pyridine-2-carbonitrile (98.0mg, 0.34 mmol) according to the procedure described for the synthesis ofthe intermediate 5-(4-fluoro-phenoxy)-4-methoxy-pyridine-2-carboxylicacid.

Yield: 94.0 mg (90%) R_(t)(HPLC): 0.60 min (Method 1)

4-Cyclopropoxy-phenol

2-(4-Cyclopropoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (800mg, 3.08 mmol) and 4-methyl-morpholine 4-oxide (1.03 g, 8.83 mmol) inTHF (100 mL) are stirred at 75° C. for 1.5 h and then for 18 h at rt.The reaction mixture is concentrated under vacuum and the residue ispurified by silica gel chromatography to afford the title compound.

Yield: 389 mg (84%)

5-(4-Cyclopropoxy-phenoxy)-4-methoxy-pyridine-2-carbonitrile

The title compound is synthesized from5-fluoro-4-methoxy-pyridine-2-carbonitrile (350 mg, 2.30 mmol) and4-cyclopropoxy-phenol (389 mg, 2.59 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-phenoxy-pyridine-2-carbonitrile.

Yield: 342 mg (53%) R_(t)(HPLC): 1.00 min (Method 1)

5-(4-Cyclopropoxy-phenoxy)-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-(4-cyclopropoxy-phenoxy)-4-methoxy-pyridine-2-carbonitrile (100 mg,0.35 mmol) according to the procedure described for the synthesis of theintermediate 5-(4-fluoro-phenoxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 622 mg (90%) R_(t)(HPLC): 0.63 min (Method 1)

4-Methoxy-5-(4-trifluoromethoxy-phenoxy)-pyridine-2-carbonitrile

The title compound is synthesized from5-fluoro-4-methoxy-pyridine-2-carbonitrile (115 mg, 0.76 mmol) and4-trifluoromethoxy-phenol (162 mg, 0.91 mmol) according to the proceduredescribed for the synthesis of the intermediate4-methoxy-5-phenoxy-pyridine-2-carbonitrile.

Yield: 140 mg (60%)

4-Methoxy-5-(4-trifluoromethoxy-phenoxy)-pyridine-2-carboxylic acid

The title compound is synthesized from4-methoxy-5-(4-trifluoromethoxy-phenoxy)-pyridine-2-carbonitrile (150mg, 0.48 mmol) according to the procedure described for the synthesis ofthe intermediate 5-(4-Fluoro-phenoxy)-4-methoxy-pyridine-2-carboxylicacid.

Yield: 120 mg (75%)

5-(2-Fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methyl ester

To 5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130 mg,0.71 mmol), triphenylphosphine (372 mg, 1.42 mmol) and 2-fluorobenzylalcohol (114 μl, 1.065 mmol) in THF (2 mL) is added diethylazodicarboxylate (646 μl, 1.42 mmol) at 0° C. The reaction mixture isallowed to warm to RT and stirred for 16 h. The resulting mixture isconcentrated under vacuum and the residue is purified by silica gelchromatography to give the title compound.

Yield: 66.0 mg (32%) R_(t)(HPLC): 0.77 min (Method 1)

5-(2-Fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid

To 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester (66.0 mg, 0.23 mmol) in THF/water/MeOH (3 mL/1 mL/1 mL) is addedLiOH (38.0 mg, 0.91 mmol), and the reaction mixture is stirred at rt.The reaction mixture is acidified to pH 4.5 with 4 N HCl andconcentrated under vacuum. The residue is dissolved in DCM and tolueneand concentrated again under reduced pressure. The product was usedwithout further purification.

Yield: 62.0 mg (99%) R_(t)(HPLC): 0.48 min (Method 1)

5-Cyclobutylmethoxy-4-methoxy-pyridine-2-carboxylic acid methyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carb-oxylic acid methyl ester (130 mg,0.71 mmol) and cyclobutyl-methanol (91.7 mg, 1.07 mmol) according to theprocedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 132 mg (74%) R_(t)(HPLC): 0.80 min (Method 1)

5-Cyclobutylmethoxy-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-cyclobutylmethoxy-4-methoxy-pyridine-2-carboxylic acid methyl ester(132 mg, 0.53 mmol) according to the procedure described for thesynthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 124 mg (quantitative) R_(t)(HPLC): 0.53 min (Method 1)

4-Methoxy-5-(1-methyl-cyclopropylmethoxy)-pyridine-2-carboxylic acidmethyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130 mg,0.71 mmol) and (1-methyl-cyclopropyl)-methanol (103 mg, 1.07 mmol)according to the procedure described for the synthesis of theintermediate 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acidmethyl ester.

Yield: 115 mg (65%) R_(t)(HPLC): 0.81 min (Method 1)

4-Methoxy-5-(1-methyl-cyclopropylmethoxy)-pyridine-2-carboxylic acid

The title compound is synthesized from5-cyclobutylmethoxy-4-methoxy-pyridine-2-carboxylic acid methyl ester(115 mg, 0.46 mmol) according to the procedure described for thesynthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 108 mg (quantitative) R_(t)(HPLC): 0.52 min (Method 1)

5-Cyclohexyloxy-4-methoxy-pyridine-2-carboxylic acid methyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130 mg,0.71 mmol) and cyclohexanol (111 μL, 1.07 mmol) according to theprocedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 171 mg (91%) R_(t)(HPLC): 0.87 min (Method 1)

5-Cyclohexyloxy-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-cyclohexyloxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (131mg, 0.49 mmol) according to the procedure described for the synthesis ofthe intermediate 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylicacid.

Yield: 124 mg (quantitative) R_(t)(HPLC): 0.57 min (Method 1)

5-(4-Fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130 mg,0.71 mmol) and (4-fluoro-phenyl)-methanol (115 μL, 1.07 mmol) accordingto the procedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 150 mg (62%) R_(t)(HPLC): 0.82 min (Method 1)

5-(4-Fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-(4-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methyl ester(150 mg, 0.44 mmol) according to the procedure described for thesynthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 177 mg (quantitative) R_(t)(HPLC): 0.82 min (Method 1)

5-Cyclopentyloxy-4-methoxy-pyridine-2-carboxylic acid methyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130 mg,0.71 mmol) and cyclopentanol (96.74, 1.07 mmol) according to theprocedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 170 mg (95%) R_(t)(HPLC): 0.87 min (Method 1)

5-Cyclopentyloxy-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-cyclopentyloxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130mg, 0.52 mmol) according to the procedure described for the synthesis ofthe intermediate 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylicacid.

Yield: 122 mg (99%) R_(t)(HPLC): 0.49 min (Method 1)

5-Isobutoxy-4-methoxy-pyridine-2-carboxylic acid methyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (118 mg,0.64 mmol) and isobutylalcohol (71.6 mg, 0.97 mmol) according to theprocedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 141 mg (92%) R_(t)(HPLC): 0.78 min (Method 1)

5-Isobutoxy-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-isobutoxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (141 mg,0.59 mmol) according to the procedure described for the synthesis of theintermediate 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylicacid.

Yield: 133 mg (quantitative) R_(t)(HPLC): 0.51 min (Method 1)

5-Cyclopropylmethoxy-4-methoxy-pyridine-2-carboxylic acid methyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130 mg,0.71 mmol) and cyclopropylmethanol (84.2 μL, 1.07 mmol) according to theprocedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 146 mg (87%) R_(t)(HPLC): 0.74 min (Method 1)

5-Cyclopropylmethoxy-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-cyclopropylmethoxy-4-methoxy-pyridine-2-carboxylic acid methyl ester(325 mg, 1.37 mmol) according to the procedure described for thesynthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 358 mg (quantitative) ESI-MS: m/z=224 (M+H)⁺ R_(t)(HPLC): 0.40min (Method 5)

5-Benzyloxy-4-methoxy-pyridine-2-carboxylic acid methyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (118 mg,0.64 mmol) and benzylalcohol (100 μL, 0.97 mmol) according to theprocedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 140 mg (80%) R_(t)(HPLC): 0.79 min (Method 1)

5-Benzyloxy-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-benzyloxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (140 mg,0.51 mmol) according to the procedure described for the synthesis of theintermediate 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylicacid.

Yield: 358 mg (99%) R_(t)(HPLC): 0.54 min (Method 1)

5-(3,3-Difluoro-cyclobutylmethoxy)-4-methoxy-pyridine-2-carboxylic acidmethyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (118 mg,0.64 mmol) and (3,3-difluoro-cyclobutyl)-methanol (150 mg, 0.82 mmol)according to the procedure described for the synthesis of theintermediate 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acidmethyl ester.

Yield: 111 mg (47%) ESI-MS: m/z=288 (M+H)⁺ R_(t)(HPLC): 1.20 min (Method5)

5-(3,3-Difluoro-cyclobutylmethoxy)-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-(3,3-difluoro-cyclobutylmethoxy)-4-methoxy-pyridine-2-carboxylic acidmethyl ester (110 mg, 0.38 mmol) according to the procedure describedfor the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 73.4 mg (70%) ESI-MS: m/z=274 (M+H)⁺ R_(t)(HPLC): 0.56 min(Method 5)

4-Methoxy-5-propoxy-pyridine-2-carboxylic acid methyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130 mg,0.71 mmol) and 1-propanol (80.0 μL, 1.07 mmol) according to theprocedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 114 mg (71%) R_(t)(HPLC): 0.69 min (Method 1)

4-Methoxy-5-propoxy-pyridine-2-carboxylic acid

The title compound is synthesized from4-methoxy-5-propoxy-pyridine-2-carboxylic acid methyl ester (114 mg,0.51 mmol) according to the procedure described for the synthesis of theintermediate 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylicacid.

Yield: 106 mg (99%) R_(t)(HPLC): 0.41 min (Method 1)

5-(2-Cyclopropyl-ethoxy)-4-methoxy-pyridine-2-carboxylic acid methylester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130 mg,0.71 mmol) and 2-cyclopropylethanol (91.7 mg, 1.07 mmol) according tothe procedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 130 mg (73%) R_(t)(HPLC): 0.82 min (Method 1)

5-(2-Cyclopropyl-ethoxy)-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-(2-cyclopropyl-ethoxy)-4-methoxy-pyridine-2-carboxylic acid methylester (130 mg, 0.52 mmol) according to the procedure described for thesynthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 122 mg (99%) R_(t)(HPLC): 0.53 min (Method 1)

4-Methoxy-5-phenethyloxy-pyridine-2-carboxylic acid methyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130 mg,0.71 mmol) and 2-phenylethanol (128 μL, 1.07 mmol) according to theprocedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 177 mg (87%) R_(t)(HPLC): 0.90 min (Method 1)

4-Methoxy-5-phenethyloxy-pyridine-2-carboxylic acid

The title compound is synthesized from4-methoxy-5-phenethyloxy-pyridine-2-carboxylic acid methyl ester (177mg, 0.62 mmol) according to the procedure described for the synthesis ofthe intermediate 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylicacid.

Yield: 168 mg (quantitative) R_(t)(HPLC): 0.63 min (Method 1)

5-(2,2-Dimethyl-propoxy)-4-methoxy-pyridine-2-carboxylic acid methylester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130 mg,0.71 mmol) and 2,2-dimethyl-propan-1-ol (93.8 mg, 1.07 mmol) accordingto the procedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 160 mg (89%) R_(t)(HPLC): 0.92 min (Method 1)

5-(2,2-Dimethyl-propoxy)-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-(2,2-dimethyl-propoxy)-4-methoxy-pyridine-2-carboxylic acid methylester (160 mg, 0.63 mmol) according to the procedure described for thesynthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 150 mg (99%) R_(t)(HPLC): 0.61 min (Method 1)

5-(1-Fluoromethyl-cyclopropylmethoxy)-4-methoxy-pyridine-2-carboxylicacid methyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (118 mg,0.64 mmol) and (1-fluoromethyl-cyclopropyl)-methanol (101 mg, 0.97 mmol)according to the procedure described for the synthesis of theintermediate 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acidmethyl ester.

Yield: 159 mg (92%) R_(t)(HPLC): 0.69 min (Method 1)

5-(1-Fluoromethyl-cyclopropylmethoxy)-4-methoxy-pyridine-2-carboxylicacid

The title compound is synthesized from5-(1-fluoromethyl-cyclopropylmethoxy)-4-methoxy-pyridine-2-carboxylicacid methyl ester (159 mg, 0.59 mmol) according to the proceduredescribed for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 150 mg (quantitative) R_(t)(HPLC): 0.43 min (Method 1)

5-Ethoxy-4-methoxy-pyridine-2-carboxylic acid methyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130 mg,0.71 mmol) and ethanol (62.1 μL, 1.07 mmol) according to the proceduredescribed for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 151 mg (100%) R_(t)(HPLC): 0.92 min (Method 1)

5-Ethoxy-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-ethoxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (151 mg, 0.71mmol) according to the procedure described for the synthesis of theintermediate 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylicacid.

Yield: 140 mg (99%) R_(t)(HPLC): 0.83 min (Method 1)

5-((S)-1-Cyclopropyl-ethoxy)-4-methoxy-pyridine-2-carboxylic acid methylester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (118 mg,0.64 mmol) and (R)-1-cyclopropyl-ethanol (83.2 mg, 0.97 mmol) accordingto the procedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 102 mg (63%)

5-((S)-1-Cyclopropyl-ethoxy)-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-((S)-1-cyclopropyl-ethoxy)-4-methoxy-pyridine-2-carboxylic acid methylester (102 mg, 0.41 mmol) according to the procedure described for thesynthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 96.0 mg (100%) R_(t)(HPLC): 0.51 min (Method 1)

5-Isopropoxy-4-methoxy-pyridine-2-carboxylic acid methyl ester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (130 mg,0.71 mmol) and propan-2-ol (81.54, 0.97 mmol) according to the proceduredescribed for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 154 mg (96%) R_(t)(HPLC): 0.62 min (Method 1)

5-Isopropoxy-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-isopropoxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (154 mg,0.68 mmol) according to the procedure described for the synthesis of theintermediate 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylicacid.

Yield: 144 mg (quantitative)

5-((R)-1-Cyclopropyl-ethoxy)-4-methoxy-pyridine-2-carboxylic acid methylester

The title compound is synthesized from5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (118 mg,0.64 mmol) and (S)-1-cyclopropyl-ethanol (83.2 mg, 0.97 mmol) accordingto the procedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 101 mg (63%)

5-((R)-1-Cyclopropyl-ethoxy)-4-methoxy-pyridine-2-carboxylic acid

The title compound is synthesized from5-((R)-1-cyclopropyl-ethoxy)-4-methoxy-pyridine-2-carboxylic acid methylester (101 mg, 0.40 mmol) according to the procedure described for thesynthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid.

Yield: 94.0 mg (99%) R_(t)(HPLC): 0.51 min (Method 1)

3-(Trifluoromethyl)cyclobutyl]methanol

To 3-(trifluoromethyl)cyclobutane-1-carboxylic acid (50 mg, 0.29 mmol)in THF (2 mL) is added CDI (57 mg, 0.36 mmol) and stirred at RT for 2 h.Sodium borohydride (12 mg, 0.31 mmol) in water (0.5 mL) is added and thereaction mixture is stirred at RT for 30 min. The reaction mixture isacidified with 1M HCl and extracted with DCM. The combined organicphases are separated and dried over Na₂SO₄, filtered and concentrated.

Yield: 45 mg (quantitative)

Methyl4-methoxy-5-{[3-(trifluoromethyl)cyclobutyl]methoxy}pyridine-2-carboxylate

The title compound is synthesized from methyl5-hydroxy-4-methoxypyridine-2-carboxylate (53 mg, 0.29 mmol) and[3-(trifluoromethyl)cyclobutyl]methanol (45 mg, 0.29 mmol) according tothe procedure described for the synthesis of the intermediate5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methylester.

Yield: 90 mg (97%)

4-Methoxy-5-{[3-(trifluoromethyl)cyclobutyl]methoxy}pyridine-2-carboxylicacid

4M aqueous NaOH solution (0.55 mL, 2.2 mmol) is added to methyl4-methoxy-5-{[3-(trifluoromethyl)-cyclobutyl]methoxy}-pyridine-2-carboxylate(350 mg, 1.10 mmol) in 5 mL methanol. The reaction mixture is stirredover night at RT. 4M aqueous HCl solution (0.5 mL) is added and thereaction mixture is stirred 30 min. The reaction mixture is evaporatedunder reduced pressure. DMF is added to the residue and the desiredcompound is purified by HPLC.

Yield: 150 mg (45%)

Methyl4-methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carboxylate

To methyl 5-hydroxy-4-methoxypyridine-2-carboxylate (100 mg, 0.55 mmol)in THF is added 3,3,3-trifluoro-2-methylpropan-1-ol (105 mg, 0.82 mmol)and triphenylphosphine (286 mg, 1.10 mmol) and followed bydiisopropylazodicarboxylate (221 mg, 1.10 mmol). The reaction mixture isstirred at RT for 3 h, The reaction mixture is evaporated under reducedpressure and the residue is purified by HPLC. The product containingfractions are combined and lyophilized.

Yield: 160 mg (quantitative)

4-Methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carboxylic acid

Aqueous 4M NaOH solution (0.52 mL, 2.08 mmol) is added to methyl4-methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carboxylate (160mg, 0.55 mmol) in methanol. The reaction mixture is stirred 2 h at RT.The reaction mixture is neutralized with aqueous 4M HCl solution andevaporated under reduced pressure. The residue is used without furtherpurification.

Yield: 150 mg (98%)

General Procedure:

Procedures for preparing compounds of the invention 1-80 are summarizedin Table 3A.

Analysis of the compounds of the invention 1-80 are summarized in Table3B.

I: To carboxylic acid (1 eq.) in DMA is added HATU (1.2 eq.) andstirred. Amine (1 eq.) and DIPEA (4.0 eq.) are added and stirred for 18h at rt. Purification by RP column (ACN/water, acidic or basicconditions) or by silica gel chromatography.

II: Carboxylic acid (1 eq.) and CDI (1.5 eq.) are stirred in DMA for 30min. at rt. Amine (1 eq.) and DIPEA (2.0 eq.) are added and stirred for3 h at rt. Purification by RP column (ACN/water, acidic or basicconditions) or by silica gel chromatography.

III: Amine (1.0 eq.), carboxylic acid (0.9 eq.), TBTU (1.0 eq.) andDIPEA (4.0 eq.) in NMP are stirred for 18 h at rt. The filtered reactionmixture is purified by RP column (ACN/water, acidic or basic conditions)or by silica gel chromatography.

TABLE 3A General procedures for preparing compounds of the invention1-80. Cpd Amine Carboxylic acid Genl. Yield No. IntermediateIntermediate Proc. % 1

I 72 2

II 82 3

III 15 4

III 13 5

I 80 6

III 49 7

I 69 8

I 33 9

I 11 10

II 82 11

III 72 12

III 63 13

III 74 14

III 72 15

III 11 16

II 52 17

III 74 18

I 69 19

III 75 20

III 24 21

II 6.9 22

III 67 23

III 44 24

II 41 25

III 44 26

III 58 27

I 58 28

III 76 29

II 48 30

III 39 31

II 62 32

III 24 33

II 56 34

III 30 35

III 42 36

III 53 37

III 37 38

I 31 39

III 51 40

III 13 41

III 29 42

I 42 43

III 49 44

III 61 45

I 50 46

III 60 47

II 61 48

III 48 49

III 54 50

I 51 51

I 36 52

III 66 53

III 54 54

III 39 55

I 64 56

II 35 57

III 67 58

I 56 59

III 42 60

III 76 61

I 26 62

III 19 63

I 29 64

III 37 65

III 34 66

III 51 67

III 60 68

I 62 69

I 17 70

III 47 71

I 27 72

III 38 73

III 60 74

III 35 75

III 57 76

III 62 77

III 38 78

I 17 79

III 43 80

I 20

TABLE 3B Analytical data for compounds of the invention 1-80. Cpd ESI-MSHPLC R_(t) HPLC No. m/z, M + H⁺ (min.) Method 1 454 0.47 1 2 437 1.07 53 405 0.83 1 4 453 0.86 1 5 436 0.44 1 6 464 0.80 3 7 468 0.44 1 8 4621.02 5 9 480 1.08 5 10 419 1.02 5 11 454 0.79 1 12 436 0.78 1 13 4240.80 1 14 423 0.87 1 15 406 0.79 1 16 406 1.52 6 17 424 1.38 2 18 4500.43 1 19 467 0.90 3 20 454 0.77 1 21 436 0.78 1 22 435 0.83 1 23 4350.83 1 24 503 1.93 6 25 398 0.75 3 26 427 0.80 3 27 480 0.50 1 28 4651.02 1 29 438 1.58 2 30 441 0.86 3 31 420 1.48 2 32 467 0.91 3 33 4741.91 6 34 440 0.83 1 35 427 0.80 3 36 386 0.73 3 37 413 0.71 3 38 4800.94 5 39 415 0.79 3 40 462 0.80 1 41 438 0.78 3 42 484 0.68 3 43 4490.81 3 44 436 0.76 1 45 463 0.73 5 46 401 0.73 3 47 436 1.36 2 48 4270.80 3 49 454 0.84 1 50 450 0.46 1 51 462 0.89 5 52 463 0.85 3 53 4270.81 3 54 472 0.77 1 55 498 0.51 1 56 504 1.84 6 57 438 0.77 3 58 4500.49 1 59 429 0.87 3 60 466 0.77 1 61 414 0.70 3 62 412 0.76 1 63 4840.70 3 64 445 0.74 3 65 387 0.65 3 66 466 0.82 1 67 398 0.74 3 68 4770.73 5 69 466 0.67 3 70 427 0.78 3 71 466 0.68 1 72 401 0.69 3 73 4340.79 3 74 400 0.81 3 75 398 0.75 3 76 372 0.66 3 77 427 0.77 3 78 3981.24 2 79 398 0.71 3 80 490 2.60

Synthesis of Nitro-Intermediates

[(R)-4-(6-Nitro-pyridin-3-yl)-piperazin-2-yl]-methanol hydrochloride

(R)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylicacid tert-butyl ester (1.73 g, 3.82 mmol) in DCM (10 mL) and 4M HCl(9.55 mL, 38.2 mmol) is stirred at RT for 2 h. The reaction mixture isconcentrated under reduced pressure.

Yield: 950 mg (91%)

[(R)-2-Hydroxymethyl-4-(6-nitro-pyridin-3-yl)-piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone

[(R)-4-(6-Nitro-pyridin-3-yl)-piperazin-2-yl]-methanol hydrochloride(60.0 mg, 0.21 mmol) and 4-methoxy-5-phenoxy-pyridine-2-carboxylic acid(42.8 mg, 0.18 mmol) in NMP (500 μL) with TBTU (70.1 mg, 0.22 mmol) andDIPEA (151 μL, 0.87 mmol) are stirred for 18 h at rt. The reactionmixture is purified by RP column chromatography (ACN/water/NH₄HCO₃). Theresidue is purified again by normal phase column chromatography(MeOH/DCM) to give the title compound.

Yield: 95 mg (93%)

[(R)-2-Hydroxymethyl-4-(6-nitro-pyridin-3-yl)-piperazin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone

The title compound is synthesized from[(R)-4-(6-nitro-pyridin-3-yl)-piperazin-2-yl]-methanol hydrochloride(60.0 mg, 0.22 mmol) and4-methoxy-5-(4-methoxy-phenoxy)-pyridine-2-carboxylic acid (48.1 mg,0.18 mmol) according to the procedure described for the synthesis of theintermediate[(R)-2-hydroxymethyl-4-(6-nitro-pyridin-3-yl)-piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone.

Yield: 102 mg (quantitative) ESI-MS: m/z=496 (M+H)⁺ R_(t)(HPLC): 0.78min (Method 1)

Procedure:

IV: Nitro intermediate (1 eq.) and Pd/C (10%) in MeOH is stirred for 20h at RT under hydrogen atmosphere. The reaction mixture is concentratedunder vacuum and purged with argon. The residue is filtered throughCelite® and washed with MeOH. The filtrate is concentrated under reducedpressure and the crude product is purified by RP column chromatography(ACN/water, basic or acidic condition).

TABLE 4 Procedures for preparing compounds of the invention 81 and 82.ESI-MS HPLC Cpd Genl. m/z R_(t) HPLC No. Nitro-Intermediate Proc. Yield% M + H⁺ (min.) Method 81

IV 47 436 0.75 1 82

IV 36 466 0.74 1

Compounds of the invention 83-89 are generally prepared by reacting acarboxylic acid intermediate with an amine intermediate under conditionssimilar to those described for General Procedure (I) in Table 3A.Analysis of the compounds of the invention 83-89 are summarized in Table5B.

Synthesis of Intermediates

4-Ethoxy-5-phenoxypicolinonitrile

To a solution of 5-fluoro-4-isopropoxypicolinonitrile (500 mg, 3.01mmol) in DMF (10 mL) stirred at RT under N2 atmosphere, is added phenol(339.85 mg, 3.61 mmol) and K₂CO₃ (1.25 g, 9.03 mmol), the resultingmixture is heated to 100° C. for 3 h. The reaction mixture is thendiluted with ethyl acetate (50 mL), washed with water and brine, driedover anhydrous Na₂SO₄, filtered and concentrated. The residue ispurified by column chromatography on silica gel.

Yield: 530 mg (73%) m/z=241 (M+H)⁺.

4-Ethoxy-5-phenoxypicolinic acid

A mixture of 4-ethoxy-5-phenoxypicolinonitrile (530 mg, 2.21 mmol) in 2Nsodium hydroxide solution (10 mL) is stirred at 100° C. overnight. Thereaction mixture is then acidified by 1N HCl to adjust pH=4 andextracted with DCM (20 mL×2). The combined organic phases are separatedand dried over Na₂SO₄, filtered and concentrated to give the desiredproduct which can be used without further purification.

Yield: 420 mg (73%) m/z=260 (M+H)⁺

tert-Butyl6-amino-4-cyclopropoxy-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-1′-carboxylate

To a stirred mixture of 5-bromo-4-cyclopropoxypyridin-2-amine (2.1 g,9.17 mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (4.25 g, 13.75 mmol) and Cs₂CO₃ (9.0 g, 27.50mmol) in dioxane (60 mL) and water (12 mL) at rt under nitrogenatmosphere is added Pd(dppf)Cl₂ (200 mg, 0.27 mmol). The resultingmixture is stirred at 90° C. for 4 h. The reaction mixture is thenpoured into ice water and extracted with DCM (50 mL×3). The combinedorganic phases are washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The residue is purified by columnchromatography on silica gel to give the desired product.

Yield: 3 g (98%) m/z=332 (M+H)⁺.

tert-Butyl4-(6-amino-4-cyclopropoxypyridin-3-yl)piperidine-1-carboxylate

To a solution of tert-butyl6-amino-4-cyclopropoxy-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-1′-carboxylate(3 g, 9.05 mmol) in EtOH (40 mL) is added Pd(OH)₂/C (2 g). The resultingreaction mixture is stirred at 25° C. under hydrogen atmosphere for 16h. The catalyst is filtered off through Celite®, and the filtrate isevaporated to dryness under reduced pressure. The residue is purified bycolumn chromatography on silica gel to give the desired product.

Yield: 1.8 g (60%) m/z=334 (M+H)⁺.

4-Cyclopropoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride

tert-Butyl4-(6-amino-4-cyclopropoxypyridin-3-yl)piperidine-1-carboxylate (1.6 g,4.8 mmol) is dissolved in a solution of HCl(g) in EtOH (10 mL). Thereaction mixture is stirred at RT for 2 h. After completion of thereaction, the solvent is removed under reduced pressure. The crudeproduct is then triturated with Et₂O to give the desired product whichcan be used without further purification.

Yield: 1 g (90%) m/z=234 (M+H)⁺.

tert-Butyl (4-propoxypyridin-2-yl)carbamate

To a stirred solution of 2-aminopyridin-4-ol (1.25 g, 11.4 mmol) inN,N-dimethylacetamide (15 mL) is added cesium carbonate (7.42 g, 22.8mmol), propylbromide (1.24 mL, 13.6 mmol) and cesium iodide (2.95 g,11.4 mmol). The resultant mixture is stirred at 100° C. for 1 day.Di-tert-butyl dicarbonate (2.74 g, 12.6 mmol) is added to the reactionmixture and stirred at 100° C. for 16 h. The reaction mixture is dilutedwith water (20 mL) and extracted with EtOAc (50 mL). Phases areseparated and the organic layer is concentrated. The crude mixture ispurified by column chromatography on silica gel to afford the desiredproduct

Yield: 787 mg (27%) m/z=253 (M+H)⁺.

tert-Butyl (5-bromo-4-propoxypyridin-2-yl)carbamate

To a stirred solution of tert-butyl (4-propoxypyridin-2-yl)carbamate(0.79 g, 3.11 mmol) in acetic acid (5 mL) is added bromine (0.40 g, 2.49mmol, in 1 mL of acetic acid) drop-wise at 0° C. After 0.5 h anadditional amount of acetic acid (8 mL) is added and the reactionmixture is allowed to warm up to room temperature. After 1 h, themixture is concentrated and purified by column chromatography on silicagel to the desired product.

Yield: 255 mg (31%) m/z=331 (M+H)⁺.

tert-Butyl6-{[(tert-butoxy)carbonyl]amino}-4-propoxy-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridinyl]-1′-carboxylate

To a solution of tert-butyl (5-bromo-4-propoxypyridin-2-yl)carbamate(254 mg, 0.77 mmol) in dioxane (4 mL) is added4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (596 mg, 1.93 mmol), sodium carbonate (2M aqueoussolution, 0.77 mL) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (56 mg,0.077 mmol). The reaction mixture is stirred at 100° C. for 24 h. Thereaction mixture is diluted with EtOAc (10 mL) and filtered through apad of SuperCell filtration agent. The filtrate is concentrated andpurified by column chromatography on silica gel to afford the desiredproduct.

Yield:333 mg (quantitative) m/z=434 (M+H)⁺.

tert-Butyl4-(6-((tert-butoxycarbonylamino)-4-propoxypyridin-3-yl)piperidine-1-carboxylate

To tert-butyl6-{[(tertbutoxy)carbonyl]amino}-4-propoxy-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-1′-carboxylate(333 mg, 0.77 mmol) in EtOH (18 mL) and EtOAc (3 mL) is added palladiumhydroxide on carbon (20% wet, 27 mg). The reaction mixture is stirredunder a hydrogen atmosphere (43 psi) for 3 days and filtered throughSuperCell filtration agent. The filtrate is concentrated under reducedpressure to afford the desired product.

Yield: 330 mg (98%) m/z=436 (M+H)⁺.

5-(Piperidin-4-yl)-4-propoxypyridin-2-amine dihydrochloride

To tert-butyl4-(6-((tert-butoxycarbonyl)amino)-4-propoxypyridin-3-yl)piperidine-1-carboxylate(330 mg, 0.76 mmol) in dichloromethane (2 mL) is added a solution of HClin dioxane (2.00 mL, 4M, 8.0 mmol). The reaction mixture is stirred for16 h and concentrated. The residue is triturated with DCM and driedunder vacuum to afford the desired product.

Yield: 233 mg quantitative.

4-Ethoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride

4-Ethoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride can besynthesized analogous to the protocol for the synthesis of5-(piperidin-4-yl)-4-propoxypyridin-2-amine dihydrochloride. Alkylationof 2-aminopyridin-4-ol with ethylbromide and subsequent Boc protectionleads to the formation of tert-butyl N-(4-ethoxypyridin-2-yl)carbamate.Bromination of tert-butyl N-(4-ethoxypyridin-2-yl)carbamate leads to thesynthesis of tert-butyl (5-bromo-4-ethoxypyridin-2-yl)carbamate.Subsequent reaction with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester leads to the formation of tert-butyl6-{[(tert-butoxy)carbonyl]amino}-4-ethoxy-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-1′-carboxylate.In the next step tert-butyl4-(6-((tert-butoxycarbonyl)amino)-4-ethoxypyridin-3-yl)piperidine-1-carboxylateis obtained via hydrogenation. Cleavage of the Boc protecting groupleads to the synthesis of 4-ethoxy-5-(piperidin-4-yl)pyridin-2-aminedihydrochloride.

tert-Butyl3-(6-aminopyridazin-3-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

To tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]-oct-2-ene-8-carboxylate(1.93 g, 5.75 mmol) and 6-bromopyridazin-3-amine (1.00 g, 5.75 mmol) in1,4-dioxane (25 mL) is added 2M aq. Na₂CO₃ solution (11.5 mL, 23.0 mmol)and Xphos 2^(nd) generation catalyst (136 mg, 0.17 mmol). The reactionmixture is degassed with argon and stirred at 100° C. for 2 h. Allvolatiles are evaporated under reduced pressure. The crude material ispurified by normal phase chromatography to obtain the title compound.

Yield: 0.80 g (46%) ESI-MS: m/z=303 (M+H)⁺

tert-Butyl-3-(6-aminopyridazin-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

To tert-butyl3-(6-aminopyridazin-3-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate(0.80 g, 2.65 mmol) in MeOH (30 mL) is added Pd/C (250 mg) undernitrogen. The reaction mixture is degassed and hydrogenated at 3 barhydrogen atmosphere at RT overnight. The reaction mixture is filteredand concentrated under reduced pressure.

Yield: 800 mg (quantitative) ESI-MS: m/z=305 (M+H)⁺

6-{8-Azabicyclo[3.2.1]octan-3-yl}pyridazin-3-amine dihydrochloride

To tert-butyl3-(6-aminopyridazin-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (800mg, 2.63 mmol) in an appropriate volume of DCM is added 4M HCl in 1,4dioxane and stirred at RT until reaction is completed. All volatiles areevaporated under reduced pressure.

Yield: 700 mg (96%) ESI-MS: m/z=205 (M+H)⁺

2-Chloro-5-fluoro-4-methoxypyridine

To 2-chloro-5-fluoropyridin-4-ol (1 g, 7.05 mmol) and K₂CO₃ (1.27 g,9.16 mmol) in DMF (10 mL) is added iodomethane (1.15 g, 8.13 mmol) atroom temperature. The resulting reaction mixture is stirred at RT for 2h. The reaction mixture is diluted with water (20 mL) and extracted withEtOAc (30 mL×2). The combined organic phases are washed with water andbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue is purified by column chromatography onsilica gel to give the desired product.

Yield:1 g (91%) m/z=162 (M+H)⁺

5-Fluoro-4-methoxypicolinonitrile

To 2-chloro-5-fluoro-4-methoxypyridine (1.0 g, 6.2 mmol), zinc cyanide(800 mg, 6.8 mmol) and dppf (34 mg, 0.62 mmol) in DMF (10 mL) stirred atRT under nitrogen atmosphere, is added Pd₂(dba)₃ (56 mg, 0.62 mmol). Thereaction mixture is stirred at 150° C. under a nitrogen atmosphere for 3h. The reaction mixture is then diluted with water (30 mL)) andextracted with EtOAc (30 mL×2). The combined organic phases are washedwith water and brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue is purified by columnchromatography on silica gel to give the desired product.

Yield: 700 mg (74%) m/z=153 (M+H)⁺.

4-Methoxy-5-(4-(trifluoromethyl)phenoxy)picolinonitrile

To 5-fluoro-4-methoxypicolinonitrile (700 mg, 4.6 mmol) in DMF (10 mL)is added 4-(trifluoromethyl)phenol (746 mg, 4.6 mmol) and K₂CO₃ (636 mg,4.6 mmol). The reaction mixture is stirred at 100° C. for 16 h. Thereaction mixture is diluted with water (20 mL) and extracted with EtOAc(20 mL×2). The combined organic phases are combined, washed with waterand brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue is purified by column chromatography onsilica gel to give the desired product.

Yield: 1 g (80%) m/z=295 (M+H)⁺.

4-Methoxy-5-(4-(trifluoromethyl)phenoxy)picolinic acid

To a solution of NaOH (1.6 g, 40 mmol) in water (20 mL) is added4-methoxy-5-(4-(trifluoromethyl)phenoxy)picolinonitrile (700 mg, 2.4mmol). The reaction mixture is stirred at 100° C. overnight. Thereaction mixture is acidified by 6M HCl to adjust pH=2, extracted withEtOAc (30 mL×2). The combined organic phases are washed with water andbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give the crude product which can be used directlywithout further purification;

Yield: 700 mg (94%) m/z=314 (M+H)⁺.

2-Chloro-5-fluoropyridin-4-ol

Under a nitrogen atmosphere at −78° C. to a stirred solution of2-chloro-5-fluoropyridine (5.0 g, 38 mmol) in tetrahydrofuran (50 mL),is added lithium diisopropylamide (24.7 mL, 49.4 mmol, 2M intetrahydrofuran) drop-wise over 30 min. The reaction mixture is stirredat −78° C. for 2 h. Afterwards a solution of trimethyl borate (7.9 g,76.03 mmol) in tetrahydrofuran (10 mL) is added drop-wise over 20 min.After addition, the reaction mixture is stirred at RT for another 2 h.The reaction mixture is cooled to 0° C. and acetic acid (6.5 mL) isadded. The reaction mixture is stirred at 0° C. for 30 min. Hydrogenperoxide (11.5 mL, 30% solution) is added drop-wise at 0° C. Thereaction mixture is stirred at RT overnight. The reaction mixture isquenched with saturated aqueous NaS₂O₄. 5N HCl is added to the reactionmixture. After extraction with EtOAc (50 mL×3), the combined organicphases are washed with water and brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue ispurified by silica gel chromatography to give the desired product.

Yield: 3.8 g (68%). m/z=149 (M+H)⁺.

2-Chloro-4-ethoxy-5-fluoropyridine

To 2-chloro-5-fluoropyridin-4-ol (2, 3.0 g, 20.33 mmol) and silver(I)carbonate (8.4 g, 30.50 mmol) in DMF (50 mL) is added iodoethane (9.51g, 61.00 mmol) at 0° C. under a nitrogen atmosphere. The reactionmixture is stirred at room temperature for 3 h. The reaction mixture isthen diluted with ethyl acetate (100 mL) and washed with water andbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue is purified by column chromatography onsilica gel to give the desired product.

Yield: 3.0 g (84%) m/z=177 (M+H)⁺.

4-Ethoxy-5-fluoropicolinonitrile

To 2-chloro-4-ethoxy-5-fluoropyridine (300 mg, 1.71 mmol) in DMF (10 mL)is added dicyanozinc (141 mg, 1.2 mmol), zinc (22.3 mg, 0.34 mmol) andPd(dppf)Cl₂ (50 mg) under a nitrogen atmosphere. The reaction mixture isstirred at 150° C. for 3 h. The reaction mixture is diluted with ethylacetate (50 mL), washed with water and brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residue ispurified by column chromatography on silica gel to give the desiredproduct.

Yield: 220 mg (78%) LC-MS: m/z 167 [M+H]⁺.

4-Ethoxy-5-(4-fluorophenoxy)picolinonitrile

To 4-fluorophenol (202 mg, 1.81 mmol) and K₂CO₃ (249 mg, 1.81 mmol) inDMF (5 mL) is added 4-ethoxy-5-fluoropicolinonitrile (200 mg, 1.2 mmol)in one portion. The reaction mixture is stirred at 100° C. for 3 h.After cooling, the reaction mixture is diluted with ethyl acetate (20mL), washed with water and brine, dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The residue is purified bycolumn chromatography on silica gel to give the desired product.

Yield: 220 mg (71%) m/z=259 (M+H)⁺.

4-Ethoxy-5-(4-fluorophenoxy)picolinic acid

A mixture of 4-ethoxy-5-(4-fluorophenoxy)picolinonitrile (500 mg, 1.94mmol) in an aqueous 2N sodium hydroxide solution (10 mL) is stirred at100° C. overnight. After cooling, the reaction mixture is acidified byaqueous 1N HCl to adjust pH=4 and extracted with DCM (20 mL×2). Thecombined organic phases are washed with water and brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive the crude desired product.

Yield: 490 mg (91%) m/z=278 (M+H)⁺.

TABLE 5A Procedures for preparing compounds of the invention 83-89. CpdAmine Carboxylic acid Genl. No. Intermediate Intermediate Proc. Yield %83

I 32 84

I 33 85

I 66 86

I 20 87

I 18 88

I 21 89

I 15

TABLE 5B Analytical data for compounds of the invention 83-89. Cpd No.ESI-MS m/z, M + H⁺ HPLC R_(t) (min.) 83 420 0.79 84 461 0.84 85 450 0.8386 463 0.84 87 518 0.97 88 438 0.80 89 465 0.82

General Procedures:

Procedures for preparing compounds of the invention 90 and 91 aresummarized in Table 6A. Analysis of the compounds of the invention 90and 91 are summarized in Table 6B.

V: To carboxylic acid (1.0 eq.) (intermediate 2 in the following table6A) in DMF is added DIPEA (3.0 eq.) and HATU (1.0 eq.) and the reactionmixture is stirred for 30 min at rt. Amine (1.0 eq) (intermediate 1 inthe following table 6A) is added and the reaction mixture is stirredovernight. The filtered reaction mixture is purified by RP columnchromatography (ACN/water+TFA or basic conditions).

TABLE 6A General procedures for preparing compounds of the invention 90and 91. Cpd amine carboxylic acid Gen. Yield No. (intermediate1)(intermediate 2) Proc. % 90

V 55 91

V 31

TABLE 6B Analytical data for compounds of the invention 90 and 91. CpdNo. ESI-MS m/z, M + H⁺ HPLC R_(t) (min.) 90 488 0.86 (Method 7) 91 4740.87 (Method 7)

Compounds 92 and 93:

TFA salt of4-Methoxy-5-[1-(4-methoxy-5-{[3-(trifluoromethyl)-cyclobutyl]methoxy}-pyridine-2-carbonyl)piperidin-4-yl]pyridin-2-amin

4-Methoxy-5-(3-trifluoromethyl-cyclobutylmethoxy)-pyridine-2-carboxylicacid (40 mg, 0.13 mmol), DIPEA (113 μL, 0.66 mmol), HATU (54 mg, 0.144mmol) and 4-methoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride(37 mg, 0.13 mmol) in DMF (2 mL) are stirred overnight at rt. Thereaction mixture is purified by RP column chromatography (ACN/water+TFA)to obtain both stereoisomers.

Yield: compound 92 (trans isomer): 5 mg (6%) HPLC R_(t): 0.50 min(method 12) and compound 93 (cis isomer): 8 mg (10%) HPLC R_(t): 0.48min (method 12), ESI-MS: m/z=495 (M+H)⁺

Compound 94:

4-Methoxy-5-{1-[4-methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carbonyl]piperidin-4-yl}pyridin-2-amine

4-Methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carboxylic acid(110 mg, 0.39 mmol), DIPEA (271 μL, 1.58 mmol), HATU (150 mg, 0.39 mmol)and 4-methoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride (121 mg,0.43 mmol) in DMF (2 mL) are stirred 2 h at rt. The reaction mixture ispurified by RP column chromatography.

Yield: 110 mg (60%) ESI-MS: m/z=469 (M+H)⁺ HPLC R_(t): 0.71 min (method13)

Enantiomers of4-Methoxy-5-(1-{4-methoxy-5-[3,3,3-trifluoro-2-methylpropoxy]pyridine-2-carbonyl}piperidin-4-yl)-pyridin-2-amine(94)4-Methoxy-5-(1-{4-methoxy-5-[(2S)-3,3,3-trifluoro-2-methylpropoxy]pyridine-2-carbonyl}piperidin-4-yl)-pyridin-2-amineand4-Methoxy-5-(1-{4-methoxy-5-[(2R)-3,3,3-trifluoro-2-methylpropoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridin-2-amine

4-Methoxy-5-{1-[4-methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carbonyl]piperidin-4-yl}pyridin-2-amine(292 mg, 0.62 mmol) is further separated by chiral supercritical fluidchromatography (SFC, supercritical carbondioxide/20 mM NH₃ in EtOH,Chiral ART,® Amylose-SC 20×250 mm, 5 μM) to obtain both enantiomers 94a(first eluting fraction) and 94b (second eluting fraction). Thestereochemistry is randomly assigned.

Yield: 70 mg (48%, compound 94a; R_(t): 5.69 min) and 74 mg (50%,compound 94b; R_(t): 6.23 min)

5-Hydroxy-4-methoxypyridine-2-carboxylic acid

Potassium hydroxide (6.28 g, 111.98 mmol) in 50 ml water is added tomethyl 5-bromo-4-methoxypyridine-2-carboxylate (5.00 g, 20.32 mmol) in1,4-dioxane (50 ml).Di-tert-Butyl-(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-biphenyl-2-yl)-phosphane(1.57 g, 3.27 mmol) and tris(dibenzylideneacetone)dipalladium(0) (949mg, 1.04 mmol) is added under argon. The reaction mixture is stirred at100° C. for 2 h. The reaction mixture is filtered and concentrated underreduced pressure. The residue is acidified with 4M HCl and the solid isfiltered. The liquid phase is concentrated and the precipitate iscollected, washed and dried.

Yield: 2.61 g (76%) ESI-MS: m/z=170 (M+H)⁺

6-[4-(6-Amino-4-methoxypyridin-3-yl)piperidine-1-carbonyl]-4-methoxypyridin-3-ol

To 5-hydroxy-4-methoxypyridine-2-carboxylic acid (100 mg, 0.59 mmol) inDMF (5 mL) is added DIPEA (407 μl, 2.36 mmol) and4-methoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride (331 mg,1.18 mmol). Then HATU (225 mg, 0.59 mmol) is added. The reaction mixtureis stirred overnight at RT and purified by reversed phase columnchromatography to afford the title compound.

Yield: 140 mg (66%) ESI-MS: m/z=359 (M+H)⁺ R_(t)(HPLC): 0.61 min (method10)

General Procedures:

A procedure for preparing compound 95 of the invention is summarized inTable 7A.

Analysis of the compound 95 of the invention is summarized in Table 7B.

VI: To6-[4-(6-amino-4-methoxypyridin-3-yl)piperidine-1-carbonyl]-4-methoxypyridin-3-ol(1.0 eq.) (intermediate 2 in the following table 7A) in dioxane is addedalcohol (2.4 eq.) (intermediate 1 in the following table 7A), TPP (2.7eq.) and DTAD (2.5 eq.). The reaction mixture is stirred at 60° C. for 1h. If the reaction shows complete conversion, the reaction mixture ispurified by RP column chromatography (ACN/water+TFA).

If reaction does not show completion, additional TPP (2.7 eq.) and DTAD(2.5 eq.) are added until conversion occurs. After each addition thereaction mixture is stirred at 60° C. for 1 h. The reaction mixture ispurified by RP column chromatography (ACN/water+TFA).

TABLE 7A General procedures for preparing compound of the invention 95.Cpd alcohol core Genl. No. (intermediate 1) (intermediate 2) Proc. Yield% 95

VI quant.

TABLE 7B Analytical data for compound of the invention 95. Cpd No.ESI-MS m/z, M + H⁺ HPLC R_(t) (min.) 95 463 0.65 (Method 13)

Alternative Preparation of Compound 1

5-{4-[5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonyl]piperazin-1-yl}-4-methoxypyridin-2-amine5-Bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridine

5-Bromo-4-methoxy-pyridin-2-ylamine (9.50 g, 46.79 mmol),hexane-2,5-dione (7.08 mL, 60.83 mmol) and p-toluenesulfonic acid (0.81g, 4.68 mmol) in toluene (80 mL) are stirred over night at 120° C. usinga Dean-Stark-apparatus. The reaction mixture is concentrated underreduced pressure, taken up in DCM and purified by silica gelchromatography (DCM).

Yield: 7.60 g (58%) ESI-MS: m/z=281 [M+H]⁺ R_(t)(HPLC): 1.13 min (method7)

1-[6-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-methoxypyridin-3-yl]piperazinebis(trifluoroacetic acid)

The reaction is performed under an argon-atmosphere.5-Bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridine (1.00 g, 3.56mmol), tert-butyl piperazine-1-carboxylate (0.73 g, 3.92 mmol),CPhos-3G-methane sulfonate (0.30 g, 0.36 mmol) and cesium carbonate(3.48 g, 10.67 mmol) in 1,4-dioxane (15 mL) are stirred over night at80° C. The reaction mixture is filtered and concentrated under reducedpressure. The residue is taken up in DCM (20 mL) and TFA (1.37 mL; 17.76mmol) is added. The reaction mixture is stirred for 3 days at RT andafter addition of the same amount TFA the reaction mixture is stirredovernight at 40° C. The reaction mixture is evaporated to dryness andused without further purification.

Yield: 1.80 g (98%) ESI-MS: m/z=287 [M+H]⁺ R_(t)(HPLC): 0.67 min (method7)

4-Methoxy-5-(piperazin-1-yl)pyridin-2-amine

1-[6-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-methoxypyridin-3-yl]piperazinebis(trifluoroacetic acid) (1.20 g, 2.33 mmol), hydroxylaminehydrochloride (0.70 g, 10.03 mmol) and triethylamine (1.00 mL, 7.11mmol) in EtOH/water (1/1; 16 mL) are stirred over night at 80° C. Theorganic solvent is removed under reduced pressure. The residue ispurified by RP-HPLC (ACN/water+NH₃).

Yield: 290 mg (60%) ESI-MS: m/z=209 [M+H]⁺ R_(t)(HPLC): 0.35 min (method11)

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonitrile

5-Fluoro-4-methoxy-pyridine-2-carbonitrile (1.00 g; 6.57 mmol),4-fluorophenol (0.88 g; 7.89 mmol) and potassium carbonate (2.00 g;14.46 mmol) are stirred in NMP at 105° C. for 1.5 hours. The reactionmixture is allowed to cool down to RT and extracted with EtOAc. Theorganic layer is washed with water and brine, separated, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residue islevigated with PE, filtered and dried in a drying oven at 60° C.

Yield: 1.54 g (96%) ESI-MS: m/z=245 [M+H]⁺ R_(t)(HPLC): 1.03 min (method7)

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carboxylic acid

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonitrile (1.54 g; 6.31 mmol)and NaOH (2 mol/L, aq. solution; 15.40 mL, 30.80 mmol) are stirred at105° C. for 10 hours. The reaction mixture is allowed to cool down to RTand is left for 3 days. The resulting precipitate is filtered andlevigated in water. The reaction mixture is warmed up to 50° C. and thepH is adjusted to pH7 using HCl (4 mol/L, aq. solution). The resultingprecipitate is filtered, washed with EE and dried in a drying oven at60° C.

Yield: 0.84 g (51%) ESI-MS: m/z=264 [M+H]⁺ R_(t)(HPLC): 0.77 min (method7)

5-{4-[5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonyl]Piperazin-1-yl}-4-methoxypyridin-2-amine

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carboxylic acid (0.40 g; 1.92mmol), HATU (0.75 g; 1.97 mmol) and DIPEA (1.16 mL; 6.72 mmol) in DMF(10 mL) are stirred for 30 minutes at RT.4-Methoxy-5-(piperazin-1-yl)pyridin-2-amine (0.52 g; 1.98 mmol) is addedand the reaction mixture is allowed to stir at RT over night. Themixture is purified by RP-HPLC (ACN/water+NH₃).

Yield: 0.31 g (36%) ESI-MS: m/z=454 [M+H]⁺ R_(t)(HPLC): 0.88 min (method11)

Alternative Preparation of Compound 39

4-Methoxy-5-{1-[4-methoxy-5-(2-methylpropoxy)pyridine-2-carbonyl]piperidin-4-yl}-pyridin-2-aminetriffluoroacetic acidMethyl-4-methoxy-5-(2-methylpropoxy)pyridine-2-carboxylate

Methyl-5-hydroxy-4-methoxypyridine-2-carboxylate (0.40 g, 2.18 mmol),2-methylpropan-1-ol (0.40 mL, 4.37 mmol) and TPP (1.72 g, 6.55 mmol) inTHF are stirred for 10 minutes at RT. The reaction mixture is cooled inan ice bath and DIAD (1.51 g; 6.55 mmol) is added. After 30 minutes thereaction mixture is purified by RP-HPLC (ACN/water+TFA).

Yield: 0.30 g (57%) ESI-MS: m/z=240 [M+H]⁺ R_(t)(HPLC): 0.85 min (method7)

4-Methoxy-5-(2-methylpropoxy)pyridine-2-carboxylic acid

Methyl-4-methoxy-5-(2-methylpropoxy)pyridine-2-carboxylate (0.30 g; 1.25mmol) and NaOH (4 mol/L, aq. solution; 0.47 mL; 1.88 mmol) in MeOH (8mL) are stirred at RT for 3 days. The pH of the reaction mixture isneutralized using HCl (4 mol/L; aq. solution) and the solvents areremoved under reduced pressure. DCM and a little amount of MeOH areadded to the residue. The insoluble material is filtered off and themother liquid is removed under reduced pressure. The residue is usedwithout further purification.

Yield: 0.20 g (71%) ESI-MS: m/z=226 [M+H]⁺ R_(t)(HPLC): 0.76 min (method7)

tert-Butyl6-amino-4-methoxy-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-1-carboxylate

The reaction is performed under an argon-atmosphere.5-Bromo-4-methoxypyridin-2-amine (7.40 g; 32.80 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(11.16 g; 36.08 mmol) and sodium carbonate (2 mol/L, aq. solution; 65.60mL; 131.21 mmol) in 1,4-dioxane (300 mL) is purged with argon. After 5minutes Xphos 2^(nd) Gen. (0.77 g; 0.98 mmol) is added and the reactionmixture is stirred over night in a sealed vial at 100° C. The reactionmixture is concentrated under reduced pressure. The residue is taken upin water and extracted several times with EtOAc. The combined organiclayers are dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue is purified by silica gel chromatography(DCM/MeOH).

Yield: 9.69 g (97%) ESI-MS: m/z=306 [M+H]⁺ R_(t)(HPLC): 0.83 min (method10)

tert-Butyl 4-(6-amino-4-methoxypyridin-3-yl)-piperidine-1-carboxylate

Under a hydrogen atmosphere (Parr-apparatus; 50 psi) tert-butyl6-amino-4-methoxy-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-1′-carboxylate(5.11 g; 16.73 mmol) and Pd/C (10%; 0.60 g) in MeOH (100 mL) are stirredat RT for 41.5 hours. Additional catalyst is added twice and and thereaction mixture is further hydrogenated. After removal of the catalystby filtration the mother liquid is concentrated under reduced pressure.The product is used without further purification.

Yield: 4.71 g (92%) ESI-MS: m/z=308 [M+H]⁺ R_(t)(HPLC): 0.82 min (method10)

4-Methoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride

tert.-Butyl 4-(6-amino-4-methoxypyridin-3-yl)-piperidine-1-carboxylate(6.90 g; 22.45 mmol) and HCl (4 mol/L; solution in 1,4-dioxane; 69.00mL; 224.47 mmol) in DCM (89.70 mL) are stirred at RT over night. Thereaction mixture is concentrated under reduced pressure. The residue islevigated in EE and filtered. The product is used without furtherpurification.

Yield: 5.30 g (84%) ESI-MS: m/z=208 [M+H]⁺ R_(t)(HPLC): 0.66 min (method11)

4-Methoxy-5-{1-[4-methoxy-5-(2-methylpropoxy)pyridine-2-carbonyl]piperidin-4-yl}-pyridin-2-aminetrifluoroacetic acid

4-Methoxy-5-(2-methylpropoxy)pyridine-2-carboxylic acid (80 mg; 0.36mmol), 4-methoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride (96mg; 0.36 mmol), DIPEA (0.24 mL; 1.42 mmol) and HATU (149 mg; 0.39 mmol)in DMF (3 mL) are stirred at RT over night. The reaction mixture ispurified by RP-HPLC (ACN/water+TFA).

Yield: 0.11 g (72%) ESI-MS: m/z=415 [M+H]⁺ R_(t)(HPLC): 0.80 min (method7)

Alternative Preparation of Compound 17

6-{1-[5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonyl]piperidin-4-yl}pyridazin-3-aminetert.-Butyl4-(6-aminopyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate

The reaction is performed under an argon-atmosphere.6-Chloropyridazin-3-amine (5.20 g; 40.14 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(13.65 g; 44.15 mmol) and sodium carbonate (2 mol/L, aq. solution; 80.28mL; 160.56 mmol) in 1,4-dioxane (350 mL) are purged with argon. After 5minutes Xphos 2^(nd) Gen. (0.95 g; 1.20 mmol) is added and the mixtureis stirred over night in a sealed vial at 100° C. The reaction mixtureis filtered and concentrated under reduced pressure. The residue istaken up in MeOH, precipitated with water and filtered. The resultingprecipitate is dried in a drying oven at 50° C. The product is usedwithout further purification.

Yield: quantitative ESI-MS: m/z=277 [M+H]⁺ R_(t)(HPLC): 0.78 min (method10)

tert-Butyl 4-(6-aminopyridazin-3-yl)-piperidine-1-carboxylate

Under an hydrogen atmosphere (Parr-apparatus; 4 bar) tert.-butyl4-(6-aminopyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (4.85g; 17.55 mmol) and Pd/C (10%; 0.50 g) in MeOH (100 mL) are stirred at RTfor 3 hours. After removal of the catalyst by filtration the motherliquid is concentrated under reduced pressure. The product is usedwithour further purification.

Yield: quantitative ESI-MS: m/z=279 [M+H]⁺ R_(t)(HPLC): 0.86 (method 11)

6-(Piperidin-4-yl)pyridazin-3-amine

tert.-Butyl 4-(6-aminopyridazin-3-yl)-piperidine-1-carboxylate (4.89 g;17.55 mmol) is stirred for 1 hour in TFA (20 mL; 259.25 mmol). Thesolvent is evaporated and the residue is purified by silica gelchromatography (DCM/MeOH+NH₃).

Yield: quantitative ESI-MS: m/z=179 [M+H]⁺ R_(t)(HPLC): injection peak(method 11)

Alternatively used amine:

6-(Piperidin-4-yl)pyridazin-3-amine dihydrochloride

The reaction is performed using a nitrogen atmosphere. tert.-Butyl4-(6-aminopyridazin-3-yl)-piperidine-1-carboxylate (1.00 g; 3.59 mmol)and HCl (4 mol/L, solution in 1,4-dioxane; 2.96 mL; 11.84 mmol) in ACN(6 mL) are stirred at 35°-40° C. for 2 hours. The reaction mixture iscooled to RT and diluted with isopropylacetate. After 10 minutes ofstirring the resulting precipitate is filtered off and dried in a dryingoven at 45° C.

Yield: quantitative ESI-MS: m/z=179 [M+H]⁺ R_(t)(HPLC): 0.94 min (method14)

6-{1-[5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonyl]piperidin-4-yl}pyridazin-3-amine

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carboxylic acid (0.70 g; 2.66mmol), HATU (1.52 g; 3.99 mmol) and DIPEA (1.83 mL; 10.64 mmol) in DMF(20 mL) are stirred for 30 minutes. 6-(Piperidin-4-yl)pyridazin-3-amine(0.71 g; 3.98 mmol) is added and the reaction mixture is allowed to stirat RT over night. The mixture is purified by RP-HPLC (ACN/water+TFA). Toremove the trifluoroacetate salt the product is taken up in water/EtOH(1.5/1) and levigated with polymer bound bicarbonate. After 30 minutesof stirring the mixture is filtered and concentrated under reducedpressure.

Yield: 180 mg (16%) ESI-MS: m/z=424 [M+H]⁺ R_(t)(HPLC): 0.77 min (method7)

Alternatively the title compound can be obtained as follows:

6-{1-[5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonyl]piperidin-4-yl}pyridazin-3-amine

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carboxylic acid (0.50 g; 1.90mmol) and CDI (0.46 g; 2.85 mmol) in NMP (1 mL) are stirred at RT for 1hour. 6-(Piperidin-4-yl)pyridazin-3-amine dihydrochloride (0.52 g; 2.09mmol) and DIPEA (0.99 mL; 5.70 mmol) are added. After stirring for 3hours the reaction mixture is diluted with water and extracted withEtOAc. The organic layer is separated, washed with water and brine,dried over MgSO₄ and filtered. The mother liquid is concentrated underreduced pressure and purified by silica gel chromatography (DCM/MeOH).The desired fractions are concentrated under reduced pressure andtreated with ACN/ethyl ether to provide the title product in solid form.

Yield: 0.27 g (34%) ESI-MS: m/z=424 [M+H]⁺ R_(t)(HPLC): 0.49 min (method1)

Alternative Preparation of Compound 37

5-{1-[5-(cyclopropylmethoxy)-4-methoxypyridine-2-carbonyl]piperidin-4-yl}-4-methoxypyridin-2-amineMethyl 5-(cyclopropylmethoxy)-4-methoxypyridine-2-carboxylate

Methyl 5-hydroxy-4-methoxypyridine-2-carboxylate (0.20 g; 1.09 mmol) andcyclopropylmethanol (884; 1.09 mmol) in THF (3 mL) are cooled in an icebath. TPP (0.32 g; 1.20 mmol) and DTAD (0.28 g; 1.20 mmol) are added.The reaction mixture is allowed to warm up to RT over night. Thereaction mixture is concentrated under reduced pressure and purified byRP-HPLC (ACN/water+TFA).

Yield: 0.18 g (70%) ESI-MS: m/z=238 [M+H]⁺ R_(t)(HPLC): 0.41 min (method12)

5-(Cyclopropylmethoxy)-4-methoxypyridine-2-carboxylic acid

Methyl 5-(cyclopropylmethoxy)-4-methoxypyridine-2-carboxylate (0.18 g;0.76 mmol) and NaOH (4 mol/L, aq. solution; 0.50 mL; 2.00 mmol) in MeOH(3 mL) are stirred at RT for 1 hour. The reaction mixture isconcentrated under reduced pressure. The residue is taken up in waterand washed with EtOAc. To the aqueous layer HCl (4 mol/L, aq. solution;0.5 mL) is added and concentrated under reduced pressure. The product isused without further purification.

Yield: 0.13 g (74%) ESI-MS: m/z=224 [M+H]⁺ R_(t)(HPLC): 0.30 min (method12)

5-{1-[5-(Cyclopropylmethoxy)-4-methoxypyridine-2-carbonyl]piperidin-4-yl}-4-methoxypyridin-2-amine

5-(Cyclopropylmethoxy)-4-methoxypyridine-2-carboxylic acid (50 mg; 0.22mmol), 4-methoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride (63mg; 0.22 mmol), DIPEA (193 μL; 1.12 mmol) and HATU (94 mg; 0.25 mmol) inDMF (2 mL) are stirred at RT over night. The resulting mixture ispurified by RP-HPLC (ACN/water+NH₃).

Yield: 45 mg (49%) ESI-MS: m/z=413 [M+H]⁺ R_(t)(HPLC): 0.87 min (method11)

Alternative Preparation of Compound 90

6-(1-{4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazin-3-aminetrifluoroacetic acid4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonitrile

5-Fluoro-4-methoxy-pyridine-2-carbonitrile (4.69 g; 30.84 mmol),4-trifluoromethylphenol (5.00 g; 30.84 mmol) and potassium carbonate(6.39 g; 46.27 mmol) are stirred in DMSO at 110° C. for 1 hour. Thereaction mixture is allowed to cool down to RT and diluted with water.The resulting precipitate is filtered, washed with water and dried in adrying oven at 50° C.

Yield: 7.40 g (82%) ESI-MS: m/z=295 [M+H]⁺ R_(t)(HPLC): 1.08 min (method10)

4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carboxylic acid

4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonitrile (7.40 g;25.51 mmol) and NaOH (4 mol/L, aq. solution; 31.44 mL, 125.75 mmol) inMeOH (100 mL) are stirred at 70° C. over night. The reaction mixture isallowed to cool down to RT and the organic solvent is evaporated. Theremaining solvent is diluted with water and adjusted to pH 3 using HCl(4 mol/L, aq. solution). The resulting precipitate is filtered and driedin a drying oven at 50° C.

Yield: 6.80 g (51%) ESI-MS: m/z=314 [M+H]⁺ R_(t)(HPLC): 0.87 min (method10)

tert-Butyl4-(6-amino-4-methylpyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate

The reaction is performed underan argon-atmosphere.6-Chloro-5-methylpyridazin-3-amine (3.00 g; 20.90 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(7.11 g; 22.98 mmol) and sodium carbonate (2 mol/L, aq. solution; 41.79mL; 83.58 mmol) in 1,4-dioxane (150 mL) is purged with argon. After 5minutes Xphos 2^(nd) Gen. (0.49 g; 0.63 mmol) is added and the mixtureis stirred over night in a sealed vial at 100° C. The reaction mixtureis concentrated under reduced pressure. The residue is taken up in waterand extracted several times with EtOAc. The combined organic layers arewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue is purified by silica gel chromatography(DCM/MeOH).

Yield: 5.20 g (86%) ESI-MS: m/z=291 [M+H]⁺ R_(t)(HPLC): 0.79 min (method10)

tert-Butyl 4-(6-amino-4-methylpyridazin-3-yl)piperidine-1-carboxylate

Under an hydrogen atmosphere (Parr-apparatus; 50 psi) tert-butyl4-(6-amino-4-methylpyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(5.20 g; 17.91 mmol) and Pd/C (10%; 0.75 g) in MeOH (100 mL) are stirredat RT for 17 hours. After removal of the catalyst by filtration themother liquid is concentrated under reduced pressure.

Yield: 5.00 g (96%) ESI-MS: m/z=293 [M+H]⁺ R_(t)(HPLC): 0.79 min (method10)

5-Methyl-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride

tert-Butyl 4-(6-amino-4-methylpyridazin-3-yl)piperidine-1-carboxylate(4.91 g; 16.79 mmol) and HCl (4 mol/L; solution in 1,4-dioxane; 73.65mL; 251.90 mmol) in 1,4-dioxane (34.37 mL) are stirred at RT over night.The reaction mixture is concentrated under reduced pressure. The residueis levigated in EtOAc and filtered. The product is used without furtherpurification.

Yield: quantitative ESI-MS: m/z=193 [M+H]⁺ R_(t)(HPLC): 0.59 min (method11)

6-(1-{4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazin-3-aminetrifluoroacetic acid

4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carboxylic acid (0.12g; 0.37 mmol), HATU (0.15 g; 0.39 mmol) and DIPEA (0.19 mL; 1.11 mmol)in DMF (3 mL) are stirred for 30 minutes.5-Methyl-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride (0.10 g;0.38 mmol), is added and the reaction mixture is allowed to stir at RTover night. The reaction mixture is purified by RP-HPLC (ACN/water+TFA).

Yield: 0.12 g (55%) ESI-MS: m/z=488 [M+H]⁺ R_(t)(HPLC): 0.86 min (method7)

Alternative Preparation of Compound 47

5-Methoxy-6-[1-(4-methoxy-5-phenoxypyridine-2-carbonyl)piperidin-4-yl]pyridazin-3-amine4-Methoxy-5-phenoxypyridine-2-carbonitrile

5-Fluoro-4-methoxy-pyridine-2-carbonitrile (0.40 g; 2.63 mmol), phenol(0.25 g; 2.66 mmol mmol) and potassium carbonate (0.54 g; 3.91 mmol) arestirred in DMSO (10 mL) at 110° C. for 2 hours. The reaction mixture isallowed to cool down to RT and diluted with water. The aqueous layer isextracted several times with EtOAc. The combined organic layers aredried over Na₂SO₄, filtered and concentrated under reduced pressure.

Yield: 0.55 g (92%) %) ESI-MS: m/z=227 [M+H]⁺ R_(t)(HPLC): 1.01 min(method 7)

4-Methoxy-5-phenoxypvridine-2-carboxylic acid

4-Methoxy-5-phenoxypyridine-2-carbonitrile (0.54 g; 2.39 mmol) and NaOH(4 mol/L, aq. solution; 3.00 mL, 12.00 mmol) in MeOH (10 mL) are stirredat 70° C. over night. The reaction mixture is allowed to cool down to RTand the organic solvent is evaporated. The remaining solvent is dilutedwith water and acidified to pH 3 using HCl (4 mol/L, aq. solution). Theresulting precipitate is filtered and dried in a desiccator.

Yield: 0.30 g (51%) ESI-MS: m/z=246 [M+H]⁺ R_(t)(HPLC): 0.72 min (method10)

tert-Butyl4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate

The reaction is performed under an argon-atmosphere.(6-Chloro-5-methoxy-pyridazin-3-yl)-carbamic acid tert.-butyl ester(4.00 g; 15.40 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(4.76 g; 15.40 mmol) and sodium carbonate (2 mol/L, aq. solution; 15.40mL; 30.81 mmol) in 1,4-dioxane (80 mL) are purged with argon. After 5minutes Xphos 2^(nd) Gen. (1.26 g; 1.54 mmol) is added and the mixtureis stirred over night in a sealed vial at 90° C. The reaction mixture isconcentrated under reduced pressure. The residue is taken up in EtOAcand washed with water and brine. The organic layer is separated andconcentrated under reduced pressure. The residue is purified by silicagel chromatography (DCM/MeOH).

Yield: 4.56 g (59%)

tert-Butyl4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)piperidine-1-carboxylate

Under an hydrogen atmosphere (Parr-apparatus; 50 psi) tert-butyl4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(4.55 g; 11.19 mmol) and Pd/C (10%; 3.57 g) in MeOH (45.5 mL) arestirred at 30° C. over night. After removal of the catalyst byfiltration the mother liquid is concentrated under reduced pressure.

Yield: 3.67 g (80%)

5-Methoxy-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride

tert-Butyl4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)piperidine-1-carboxylate(3.67 g; 8.98 mmol) and HCl (4 mol/L; solution in 1,4-dioxane; 55.05 mL;134.76 mmol) in 1,4-dioxane (26.69 mL) are stirred at RT over night. Thereaction mixture is concentrated under reduced pressure. The residue islevigated in EtOAc and filtered. The product is used without furtherpurification.

Yield: 2.07 g (82%) ESI-MS: m/z=209 [M+H]⁺ R_(t)(HPLC): 0.60 min (method11)

5-Methoxy-6-[1-(4-methoxy-5-phenoxypyridine-2-carbonyl)piperidin-4-yl]pyridazin-3-amine

4-Methoxy-5-phenoxypyridine-2-carboxylic acid (0.10 g; 0.41 mmol), HATU(0.16 g; 0.419 mmol) and DIPEA (0.18 mL; 1.05 mmol) in DMF (3 mL) arestirred for 30 minutes. 5-Methoxy-6-(piperidin-4-yl)pyridazin-3-aminedihydrochloride (0.12 g; 0.41 mmol), is added and the reaction mixtureis allowed to stir at RT over night. The mixture is purified by RP-HPLC(ACN/water+NH₃).

Yield: 0.09 g (53%) ESI-MS: m/z=436 [M+H]⁺ R_(t)(HPLC): 0.63 min (method13)

Alternative Preparation of Compound 29

6-{1-[5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonyl]piperidin-4-yl}-5-methylpyridazin-3-aminetrifluoroacetic acid

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carboxylic acid (60 mg; 0.23mmol), 5-methyl-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride (60mg; 0.23 mmol) HATU (95 mg; 0.25 mmol) and DIPEA (0.12 mL; 0.68 mmol) inDMF (3 mL) are stirred at RT for 1 hour. The mixture is purified byRP-HPLC (ACN/water+TFA).

Yield: 73 mg (59%) ESI-MS: m/z=438 [M+H]⁺ R_(t)(HPLC): 0.82 min (method7)

Alternative Preparation of Compound 91

5-Methoxy-6-(1-{5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridazin-3-aminetrifluoroacetic acid5-[4-(Trifluoromethyl)phenoxy]pyridine-2-carbonitrile

2-Cyano-5-fluoropyridine (3.54 g; 28.99 mmol), 4-trifluoromethyl-phenol(4.70 g; 28.99 mmol) and potassium carbonate (6.01 g; 43.49 mmol) arestirred in DMSO (150 mL) at 110° C. for 1 hour. The reaction mixture isdiluted with water and extracted with EtOAc. The organic layer is washedwith water, separated, dried over Na₂SO₄, filtered and concentratedunder reduced pressure.

Yield: quantitative ESI-MS: m/z=265 [M+H]⁺ R_(t)(HPLC): 1.03 min (method10)

5-[4-(Trifluoromethyl)phenoxy]pyridine-2-carboxylic acid

5-[4-(Trifluoromethyl)phenoxy]pyridine-2-carbonitrile (3.87 g; 14.65mmol) and NaOH (4 mol/L, aq. solution; 18.31 mL, 73.24 mmol) in MeOH (50mL) are stirred at 70° C. over night. The reaction mixture isconcentrated under reduced pressure. The residue is taken up in waterand acidified to pH3 using HCl (4 mol/L, aq. solution). The organicsolvent is completly evaporated and the resulting precipitate isfiltered. The residue is taken up in DCM, filtered and dried in a dryingoven at 50° C.

Yield: quantitative ESI-MS: m/z=284 [M+H]⁺ R_(t)(HPLC): 0.68 min (method11)

5-Methoxy-6-(1-{5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridazin-3-aminetrifluoroacetic acid

5-[4-(Trifluoromethyl)phenoxy]pyridine-2-carboxylic acid (0.10 g; 0.35mmol), HATU (0.15 g; 0.39 mmol) and DIPEA (0.19 mL; 1.11 mmol) in DMF (3mL) are stirred for 30 minutes at RT.5-Methoxy-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride (0.11 g;0.37 mmol) is added and the reaction mixture is allowed to stir at RTover night. The mixture is purified by RP-HPLC (ACN/water+TFA).

Yield: 0.06 g (31%) ESI-MS: m/z=474 [M+H]⁺ R_(t)(HPLC): 0.87 min (method7)

Alternative Preparation of Compound 31

6-[1-(4-Methoxy-5-phenoxypyridine-2-carbonyl)piperidin-4-yl]-5-methylpyridazin-3-aminetrifluoroacetic acid

4-Methoxy-5-phenoxypyridine-2-carboxylic acid (60 mg; 0.23 mmol),5-methyl-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride (55 mg;0.23 mmol), HATU (95 mg; 0.25 mmol) and DIPEA (0.12 mL; 0.68 mmol) inDMF (3 mL) are stirred for 1 hour at RT. The mixture is purified byRP-HPLC(ACN/water+TFA).

Yield: 69 mg (57%) ESI-MS: m/z=420 [M+H]⁺ R_(t)(HPLC): 0.81 min (method7)

Assessment of Biological Activity

High Throughput Screening Assay

This screening assay measures TRPC6 (transient receptor potential cationchannel, subfamily C, member 6) ion channel activation via additioneither of the commercially available DAG ligand analogue OAG(1-oleoyl-2-acetyl-sn-glycerol) or of the TRPC6 agonist1-[1-(4,5,6,7,8-pentahydrocyclohepta[2,1-d]thiophen-2-ylcarbonyl)-4-piperidyl]-3-hydrobenzimidazol-2-one(GSK1702934A). The assay utilizes a FLIPR fluorescent calcium sensor4-(6-Acetoxymethoxy-2,7-difluoro-3-oxo-9-xanthenyl)-4′-methyl-2,2′-(ethylenedioxy)dianiline-N,N,N′,N′-tetraaceticacid tetrakis(acetoxymethyl) ester (Fluo4/AM) membrane potential (FMP)dye from Molecular Devices, which is a voltage sensitive indicator witha fluorescent quencher. Changes (increases) in intracellular membranecalcium concentration potential as measured by the fluorescent signalincrease during membrane depolarization provide a measurement of channelactivity.

The commercially available HEK293/TREx line (Invitrogen) was stablytransfected with a TRPC6 construct and screened by conventional calciumimaging to find clones with TRPC6 expression following stimulation with1 μg/ml tetracycline. These cells were maintained in the growth mediumrecommended by the manufacturer supplemented with 100 μg/ml hygromycinto promote retention of the TRPC6 construct. After growing to nearconfluency, cells were plated at a density of “35,000 cells/well in 384well CellBind plates (Corning) in the presence of 1 μg/ml tetracycline,and allowed to grow for 20-30 hrs. A nearly confluent monolayerresulted. Growth media was removed from the wells and cells were thenloaded with 25 mL Fluo4/AM diluted in Ringer's Solution (6.5 g NaCl,0.42 g KCl, 0.25 g CaCl2 and 0.2 g of sodium bicarbonate; pH 7.4)supplemented with 1% Pluronic F-127 to a final concentration of 0.5 μMand incubated for 60 min, at room temperature. Dye solution was thenremoved from the cells by inverting plates with a sharp flick, andreplaced with 25 μl Ringer's. Following “0.5 hour for recovery fromloading, cells were assayed using the Hamamatsu FDSS 6000 system, whichpermitted illumination at 485 nm. Frames were acquired at a rate of 0.2Hz. During the assay, the plates were continuously vortexed, withpipette mixing of wells following addition of each reagent. For thescreening assay, 26 μl of a diluted compound stock (at 50 μM) was addedto each well for 2 minutes following the collection of a short (4 frame)baseline. 13 μl of agonist solution consisting of 125 nM GSK1702934Adiluted in high-Ca2+Ringer solution (containing 90 mm Ca2+) was thenadded to each well, achieving a final concentration of 20 mm Ca2+ and 10μM test compound. Data was collected for “3 minutes following additionof high Ca2+Ringer. The fluorescent ratio for each well was divided bythe initial fluorescent intensity for that well and the overall responsewas determined by averaging the fluorescent ratio of the last 4 framesacquired during the experiment excepting the final frame. Negative andPositive controls were included on each plate. Negative controls wellsconsisted of HEK293/TREx TRPC6 cells exposed to assay buffer and agonistsolution, but no test compound. Positive control consisted of wellsconsisted of HEK293/TREx TRPC6 cells exposed to 25 μM3-[(2-chlorophenoxy)methyl]phenyl piperidyl ketone (Chembridge) dilutedin Ringer's solution and agonist solution. These controls defined zeropercent and 100 percent block respectively, and intensity of each wellwas normalized to these values.

IC50s were determined using the above fluorescence method with theexception that instead of testing the compounds at 10 μM, compounds weretested at final concentrations of 20 μM, 6.667 μM, 2.222 μM, 0.741 μM,0.247 μM, 0.082 μM, and 0.027 μM. Compounds were tested in triplicate atall concentrations. Standard software was used to fit IC50 curves.

TABLE 8 Antagonist effects of compounds of the invention against TRPC6(IC₅₀) Compound No. TRPC6 IC₅₀ (nM)  1 <27  2 <27  3 <27  4 <27  5 27  627  7 27  8 27  9 27 10 27 11 27 12 27 13 27 14 27 15 27 16 27 17 29 1831 19 32 20 42 21 43 22 46 23 54 24 67 25 70 26 71 27 75 28 100 29 11030 110 31 120 32 130 33 82 34 85 35 94 36 97 37 160 38 170 39 170 40 17041 180 42 140 43 140 44 140 45 150 46 160 47 220 48 250 49 250 50 47 51290 52 190 53 210 54 220 55 220 56 290 57 300 58 100 59 340 60 440 61500 62 550 63 670 64 820 65 830 66 840 67 560 68 630 69 630 70 640 71850 72 910 73 1300 74 1400 75 1500 76 1800 77 2200 78 2800 79 3700 80<27 81 71 82 180 83 98 84 300 85 320 86 350 87 620 88 750 89 2100 90 36491 414 92 635 93 595 94a 343 94b 351 95 445

The biological activity of the claimed compounds can also be shown usinga TRPC6 patch clamp assay.

Methods of Therapeutic Use

The inhibition of TRPC6 is an attractive means for preventing andtreating a variety of diseases or conditions that are exacerbated byTRPC6 activity. The compounds disclosed herein effectively inhibit TRPC6activity. In particular, the compounds of the invention are selectiveion channel inhibitors and have good metabolic stability in humanmicrosomes. More particularly, the compounds of the invention have verygood potency and selectivity on the TRPC6 channel as compared to otherTRP channels including TRPC3, TRPC5 and TRPC7. Thus, the compounds ofthe invention are useful for the treatment of diseases and conditions asdescribed in the Background and Detailed Description section, includingthe following conditions and diseases:

cardiac conditions (e.g., cardiac hypertrophy), hypertension (e.g.,primary or secondary), pulmonary arterial hypertension (e.g., IPAH), aneurodegenerative disease or disorder (e.g., Alzheimer's disease (AD),Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis(ALS), and other brain disorders caused by trauma or other insultsincluding aging), inflammatory diseases (e.g., asthma, chronicobstructive pulmonary disease, rheumatoid arthritis, osteoarthritis,inflammatory bowel disease, multiple sclerosis, and disorders of theimmune system), preeclampsia and pregnancy-induced hypertension, kidneydiseases (focal segmental glomerulosclerosis, nephrotic syndrome,diabetic nephropathy, renal insufficiency, end stage renal disease,minimal change disease), ischemia or an ischemic reperfusion injury,cancer, IPF (idiopathic pulmonary fibrosis), ARDS (acute respiratorydisease syndrome), and diabetes metabolic disorders such as diabetes.Methods for preventing or treating any of the foregoing or followingdiseases and conditions include treating any of the symptoms associatedwith these diseases or conditions. For example, methods for treatingkidney disease contemplate treating symptoms including, but not limitedto, secondary hypertension, proteinuria, lipiduria,hypercholesterolemia, hyperlipidemia, and coagulation abnormalities.

Because of the important role that calcium regulation plays in manycellular processes including cellular activation, cytoskeletalrearrangement, gene expression, cellular trafficking and apoptotic celldeath, calcium dyshomeostasis is implicated in the many diseases anddisorders. These diseases and disorders include neurological andneurodegenerative diseases and disorders; inflammatory diseases anddisorders such as inflammatory bowel disease and Crohn's disease; kidneydisease such as hypercalcemia, kidney stones, and polycystic kidneydisease; metabolic diseases and disorders including obesity anddiabetes; liver and kidney diseases and disorders; chronic kidneydisease, cardiovascular diseases and disorders including hypertension;respiratory diseases including COPD, IPAH, asthma, and emphysema; andcancers, including cancers of the brain, breast, kidney, cervix,prostate, gastrointestinal tract, (e.g., gastric cancer or stomachcancer), skin, and epithelia.

These disorders have been well characterized in man, but also exist witha similar etiology in other mammals, and can be treated bypharmaceutical compositions of the present invention.

Accordingly, a compound of the invention, as described herein, or apharmaceutically acceptable salt thereof may be used for the preparationof a medicament for treating a disease or disorder mediated by TRPC6,including those mentioned above and in the Background and DetailedDescription sections.

For therapeutic use, the compounds of the invention may be administeredvia a pharmaceutical composition in any conventional pharmaceuticaldosage form in any conventional manner. Conventional dosage formstypically include a pharmaceutically acceptable carrier suitable to theparticular dosage form selected. Routes of administration include, butare not limited to, intravenously, intramuscularly, subcutaneously,intrasynovially, by infusion, sublingually, transdermally, orally,topically or by inhalation. The preferred modes of administration areoral and intravenous.

The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutical compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. In one embodiment, for example,multiple compounds of the present invention can be administered.Advantageously, such combination therapies utilize lower dosages of theconventional therapeutics, thus avoiding possible toxicity and adverseside effects incurred when those agents are used as monotherapies.Compounds of the invention may be physically combined with theconventional therapeutics or other adjuvants into a singlepharmaceutical composition. Advantageously, the compounds may then beadministered together in a single dosage form. In some embodiments, thepharmaceutical compositions comprising such combinations of compoundscontain at least about 5%, but more preferably at least about 20%, of acompound of the invention (w/w) or a combination thereof. The optimumpercentage (w/w) of a compound of the invention may vary and is withinthe purview of those skilled in the art. Alternatively, the compounds ofthe present invention and the conventional therapeutics or otheradjuvants may be administered separately (either serially or inparallel). Separate dosing allows for greater flexibility in the dosingregimen.

As mentioned above, dosage forms of the compounds of this invention mayinclude pharmaceutically acceptable carriers and adjuvants known tothose of ordinary skill in the art and suitable to the dosage form.These carriers and adjuvants include, for example, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, buffer substances,water, salts or electrolytes and cellulose-based substances. Preferreddosage forms include tablet, capsule, caplet, liquid, solution,suspension, emulsion, lozenges, syrup, reconstitutable powder, granule,suppository and transdermal patch. Methods for preparing such dosageforms are known (see, for example, H. C. Ansel and N. G. Popovish,Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea andFebiger (1990)). Dosage levels and requirements for the compounds of thepresent invention may be selected by those of ordinary skill in the artfrom available methods and techniques suitable for a particular patient.In some embodiments, dosage levels range from about 1-1000 mg/dose for a70 kg patient. Although one dose per day may be sufficient, up to 5doses per day may be given. For oral doses, up to 2000 mg/day may berequired. As the skilled artisan will appreciate, lower or higher dosesmay be required depending on particular factors. For instance, specificdosage and treatment regimens will depend on factors such as thepatient's general health profile, the severity and course of thepatient's disorder or disposition thereto, and the judgment of thetreating physician.

The compounds of the invention may be used alone or in combination ofone or more additional therapeutic agents. Nonlimiting examples ofadditional therapeutic agents may include:

angiotensin II receptor antagonists (angiotensin receptor blockers(ARBs)) such as candesartan, eprosartan, candesartan, irbesartan,losartan, olmesartan, telmisartan, valsartan, azilsartan, and medoxomil;

angiotensin converting enzyme inhibitors (e.g., benazepril, captopril,enalapril, fosinopril, lisinopril, moexipril, and perindopril);

antidiabetics such as alpha-glucosidase inhibitors (e.g., miglitol andacarbose), amylin analogs (e.g., pramlintide), dipeptidyl peptidase 4inhibitors (e.g., alogliptin, sitagliptin, saxagliptin, andlinagliptin), incretin mimetics (e.g., liraglutide, exenatide,liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide),insulin, meglitinides (e.g., repaglinide and nateglinide), biguanides(e.g., metformin); SGLT-2 inhibitors (e.g., canagliflozin,empagliflozin, and dapagliflozin), sulfonylureas (e.g., chlorpropamide,glimepiride, glyburide, glipizide, glyburide, tolazamide, andtolbutamide), and thiazolidinediones (e.g., rosiglitazone andpioglitazone);

bronchodilators including short-acting and long-action beta agonists(e.g., albuterol, levalbuterol, salmeterol, formoterol, andarformoterol) and short- and long-acting anticholinergics (ipratropium,tiotropium, umeclidinium, glycopyrrolatei), and aclidinium).

steroids such as fluticasone and budesonide;

When used as combination treatment of a pharmaceutical combination, thecompounds of the invention and the one or more additional agents can beadministered in the same dosage form or different dosage forms. Thecompounds of the invention and the one or more additional agents can beadministered simultaneously or separately, as part of a regimen.

What is claimed is:
 1. A compound selected from the group consisting ofany one of compounds selected from the group consisting of:[4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone,[4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone,[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone,[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methanone,[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone,[4-(6-Amino-4-ethoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(phenoxy)-pyridin-2-yl]-methanone,5-Ethoxy-6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridazin-3-amine,and6-(1-{4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazin-3-amine,or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, wherein the compound is[4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone,or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, wherein the compound is[4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone,or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein the compound is[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone,or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, wherein the compound is[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methanone,or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, wherein the compound is[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone,or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, wherein the compound is[4-(6-Amino-4-ethoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(phenoxy)-pyridin-2-yl]-methanone,or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, wherein the compound is5-Ethoxy-6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridazin-3-amine,or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1, wherein the compound is6-(1-{4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazin-3-amine,or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising any one of the compounds of claim 1, or apharmaceutically acceptable salt thereof, and optionally apharmaceutically acceptable excipient.
 11. A method for treating adisease or disorder that can be alleviated by TRPC6 inhibition, themethod comprising administering a therapeutically effective amount of acompound according claim 1, or a pharmaceutically acceptable saltthereof, to patient in need thereof, wherein the disease or disorder isselected from the group consisting of cardiac hypertrophy, ischemia,ischemic reperfusion injury, hypertension, pulmonary arterialhypertension, idiopathic pulmonary arterial hypertension, restenosis,chronic obstructive pulmonary disease, cystic fibrosis, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), trauma induced brain disorders, asthma, chronicobstructive pulmonary disease, rheumatoid arthritis, osteoarthritis,inflammatory bowel disease, multiple sclerosis, muscular dystrophy,Duchenne's muscular dystrophy, preeclampsia and pregnancy-inducedhypertension, non-alcoholic steatohepatitis, minimal change disease,focal segmental glomerulosclerosis (FSGS), nephrotic syndrome, diabeticnephropathy or diabetic kidney disease (DKD), chronic kidney disease,renal insufficiency, end stage renal disease, ischemia or an ischemicreperfusion injury, idiopathic pulmonary fibrosis (IPF), acuterespiratory disease syndrome (ARDS), emphysema and diabetes.
 12. Themethod according to claim 11, wherein the disease or disorder is focalsegmental glomerulosclerosis (FSGS), chronic kidney disease, idiopathicpulmonary fibrosis (IPF), or acute respiratory disease syndrome (ARDS).13. A pharmaceutically acceptable salt form of the compound of claim 1,wherein the compound is[4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone.14. A pharmaceutically acceptable salt form of the compound of claim 1,wherein the compound is[4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone.15. A pharmaceutically acceptable salt form of the compound of claim 1,wherein the compound is[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone.16. A pharmaceutically acceptable salt form of the compound of claim 1,wherein the compound is[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methanone.17. A pharmaceutically acceptable salt form of the compound of claim 1,wherein the compound is[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone.18. A pharmaceutically acceptable salt form of the compound of claim 1,wherein the compound is[4-(6-Amino-4-ethoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(phenoxy)-pyridin-2-yl]-methanone.19. A pharmaceutically acceptable salt form of the compound of claim 1,wherein the compound is5-Ethoxy-6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridazin-3-amine.20. A pharmaceutically acceptable salt form of the compound of claim 1,wherein the compound is6-(1-{4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazin-3-amine.21. A compound of claim 1, wherein the compound is[4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone.22. A compound of claim 1, wherein the compound is[4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone.23. A compound of claim 1, wherein the compound is[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone.24. A compound of claim 1, wherein the compound is[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methanone.25. A compound of claim 1, wherein the compound is[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone.26. The compound of claim 1, wherein the compound is[4-(6-Amino-4-ethoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(phenoxy)-pyridin-2-yl]-methanone.27. A compound of claim 1, wherein the compound is5-Ethoxy-6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridazin-3-amine.28. A compound of claim 1, wherein the compound is6-(1-{4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazin-3-amine.